3.2. Risk of bias
Results of risk of bias are showed in Figure 2. For random sequence
generation, three studies which reported use a computer generated
randomization sequence and sealed envelopes, were considered as low risk
of bias (2, 6, 13). One study was considered as high risk of bias
because of no exact grouping in trial (5). And others did not referred
to exact methods, which were considered as unclear of bias. Six studies
used sealed envelope method of randomization, random code generated by
computer and a card-selection system to assess allocation concealment,
and these studies were considered as low risk of bias. Other four
studies were considered high risk of bias (4, 5, 13, 15). Because in
these studies, the treatment were performed crosswise. Because of
different volumes of two treatments, there were 2 studies consider as
high risk of performance bias (7, 14). And there were two studies were
considered as low risk of detection bias (4, 5). Others were not
referred to detection methods, which were considered as unclear of bias.
And all studies had no incomplete outcome data and no selective
reporting, which were low risk of reporting bias.
Reduction of ICP
Clinically, HTS and mannitol are usually given as a bolus therapy. And
the onset action of mannitol and HTS on ICP begin within minutes, and
duration of both are to 6 h - 8 h (17). Therefore the detecting time
point would not be too long. In eligible trials, interested data of
changes of ICP were at baseline and after treatment. However, time
points in included studies were not very coincident. In that case, the
first reported records of ICP changes were extracted for general
meta-analysis. The time point of first recorded change of ICP was o.5 h
in seven studies (4, 6, 7, 13, 15, 16, 18), 1 h in one study (14), day 1
in one study (2) and the last study only reported the maximum reduction
of ICP (5). In general meta-analysis of ICP reduction, a fixed-effect
model was applied because of low heterogeneity (p = 0.93,
I2 = 0%, no heterogeneity). The pooled mean of ICP
reduction, comparing HTS to mannitol, was 0.76 mm Hg (95% CI: 0.44 to
1.08, p < 0.00001). Results indicated that HTS was more
effective than mannitol for reduction of elevated ICP in the general
meta-analysis (Fig 3).
Moreover, there were other reported time points of ICP reduction in
eligible studies. Therefore, for a more precise result, we performed
meta-analyses based on reduction of ICP at different time points (Fig
4). Seven studies provided complete ICP data at baseline and 0.5 h after
intervention (4, 6, 7, 13, 15, 16, 18). A fixed-effect model was applied
(0.5 h subgroup, p = 0.87, I2 = 0%, no
heterogeneity), and the pooled results showed mean of ICP reduction,
comparing HTS to mannitol, was 0.74 mm Hg (95% CI: 0.41 to 1.07, p
< 0.0001). Six studies reported complete ICP data at baseline
and 1 h after intervention (4, 7, 13, 14, 16, 18). Then a fixed-effect
model was applied (1 h subgroup, p = 0.10, I2 = 46%,
moderate heterogeneity), and the pooled results showed mean of ICP
reduction, comparing HTS to mannitol, was 1.60 mm Hg (95% CI: 0.77 to
2.44, p = 0.0002). Four studies provided complete ICP data at baseline
and 2 h after intervention (4, 6, 7, 13). In 2 h subgroup, a
random-effect model was applied (p = 0.05, I2 = 62%,
large heterogeneity), and the pooled results showed mean of ICP
reduction, comparing HTS to mannitol, was 1.50 mm Hg (95% CI: 0.15 to
2.85, p = 0.03). Based on data from included studies, only data at 0.5
h, 1 h and 2 h were eligible for meta-analysis. And all results
indicated that HTS was more effective than mannitol in reducing elevated
ICP in earlier stage.
Change of secondary outcomes
Also, some studies reported changes of CPP, MAP, serum sodium, serum
osmolarity, HCT and HR after intervening with mannitol or HTS. As
limitation, eligible data extracted for meta-analysis were from baseline
and time of first record after treatment.
Changes of CPP were reported in eight studies, and a random-effect model
was applied (p < 0.00001, I2 = 88%, extreme
heterogeneity). The pooled results showed mean of CPP elevation,
comparing HTS to mannitol, was 5.02 mm Hg (95% CI: 1.09 to 8.95, p =
0.01) (Fig 5) (2, 4, 6, 13-16, 18). Seven studies reported changes of
serum sodium (2, 4, 6, 7, 14-16). A random-effect model was applied (p
< 0.00001, I2 = 96%, extreme
heterogeneity), and the pooled results showed mean of serum sodium
elevation, comparing HTS to mannitol, was 6.51 mmol/L (95% CI: 3.23 to
9.79, p < 0.0001) (Fig 5). Changes of serum osmolarity were
reported in six studies (2, 4, 14-16, 18). A random-effect model was
applied (p < 0.00001, I2 = 92%, extreme
heterogeneity), and the pooled results showed mean of serum sodium
elevation, comparing HTS to mannitol, was 8.22 mOsm/kg (95% CI: 2.92 to
13.52, p = 0.002) (Fig 5). Pooled results indicated that elevation of
CPP, serum sodium and serum osmolarity were all more in HTS group than
in mannitol group in treatment of elevated ICP.
As for MAP, there were seven studies reported the changes (2, 4, 6,
14-16, 18). A random-effect model was applied (p < 0.00001,
I2 = 90%, extreme heterogeneity), and the pooled
results showed mean of MAP elevation, comparing HTS to mannitol, was
1.86 mm Hg (95% CI: -1.73 to 5.44, p = 0.31) (Fig 5). Changes of HCT
were reported only in three studies (6, 16, 18). A fixed-effect model
was applied (p = 0.31, I2 = 15%, no heterogeneity),
and the pooled results showed mean of HCT change, comparing HTS to
mannitol, was -0.21 (95% CI: -1.59 to 1.17, p = 0.76) (Fig 5). Three
studies referred to outcomes of change of HR (2, 16, 18). A fixed-effect
model was applied (p = 0.32, I2 = 13%, no
heterogeneity), and the pooled results showed mean of HR change,
comparing HTS to mannitol, was 1.4 beats/minute (95% CI: -1.00 to 3.80,
p = 0.25) (Fig 5). These pooled results demonstrated that there was no
statistical significance in change of MAP, HCT and HR between two
interventions.
Sensitivity analysis
Sensitivity analysis was performed for present meta-analyses by removing
each study in turn and reran a new meta-analysis. In meta-analysis
groups of ICP-general, ICP-0.5 h, CPP, serum sodium, serum osmolarity,
remained pooled results were not significantly altered, which indicated
our results were stable and receivable. Because of limited studies,
sensitivity analysis were not performed in meta-analyses of ICP-2 h,
HCT, and HR. However, in meta-analysis of MAP, after removing study of
Huang Xue 2015 or Patil, H 2019, pooled results were changed
respectively (0.00 mm Hg (95% CI: -1.11 to 1.11, p = 1.00) p =
< 0.0001, I2 = 83%; 0.78 mm Hg (95% CI:
-0.26 to 1.83, p = 0.14) p = < 0.00001, I2 =
89%) (4, 16). Moreover, in ICP-1 h meta-analysis, pooled results
changed to 1.80 mm Hg (95% CI: 0.95 to 2.65, p < 0.0001) p =
0.61, I2 = 0%, when removing study of Francony, G.
2008 (7).
Publication bias
Results of contour-enhanced funnel plot showed there was only one
imputed study (Fig 6). And results of mean difference in observed group
and observed + imputed group were not significant difference (0.761 vs
0.775) (S 1). Therefore, there was no evident publication bias. In
addition, results of Egger’s test (P > 0.7481) suggested an
absence of publication bias as well (S 2).
Reviewed and summarized previous similar systematic reviews
and meta-analyses
In addition, we summarized and extracted some main items and conclusions
of previous similar systematic reviews and meta-analyses (Table 2).
Results showed that there were seven studies about the similar subject.
Three of them demonstrated HTS was more effective than mannitol for
treatment of elevated ICP (19-21). The other four studies indicated
there was no significant difference between HTS and mannitol in ICP
reduction (22-25). As rating by AMSTAR 2, only one studies was rated as
“Moderate” (24), even there were three rated “Critical Low” (S 3)
(19, 20, 25). Results of methodological evaluation by AMSTAR 2
demonstrated that all previous studies might not have high qualities,
and the confidence was deficient.
Disscussion
In present systematic review and meta-analysis, for a meticulous result,
not only a general meta-analysis but also analyses of different time
points were performed. Finally, a conclusion was drew that HTS was more
effective than mannitol for reduction of elevated ICP in earlier stage
(0.5 h, 1.0 h, and 2 h). And the high quality review was performed on
the basis of AMSTAR 2. Of note, although results of heterogeneity showed
that ICP could be ignored in respective analysis, we still preformed
sensitivity analysis to show credibility and stability. Finally, all
results preferred the efficacy of HTS more than mannitol.
As aforementioned, we researched and summarized seven previous similar
meta-analyses. The final conclusions about treatment with HTS or
mannitol in reduction of elevated ICP were always vary and the problem
which was the most proper approach remained controversial. The
heterogeneous results were not surprising given methodological
differences, including various definitions of ICP treatment thresholds
and treatment failure thresholds, sampling time to determine ICP change,
formulation and osmolar loads of solutions, and diverse study
populations. Although there are several imperfect details in these
studies, previous meta-analyses are worth leaning and of great
significance.
It was demonstrated that recommended target CPP value for favorable
outcomes was between 60 mm Hg and 70 mm Hg (8). Elevated ICP could lead
to reduction of CPP which might cause a poor prognosis. And elevated ICP
could decrease CPP to the point where cerebral blood flow (CBF) might
fall to the level that induced ischemia and secondary brain injury.
Therefore, not only reduction of ICP but also elevation of CPP in
hyperosmolar agent treatment were very important. Our results showed
that both HTS and mannitol could increase CPP from the pretreatment
level, moreover HTS did it better. However, the I2 of
pooled results was 88%, which means there was an extreme heterogeneity.
Following a sensitive analysis, study of Jagannatha, A.T (2) who had the
distinct results from others was excluded, but pooled results of other
studies showed I2 was still over 75%. And the pooled
result is similar to the former. A reason of heterogeneity might be that
difference of CPP between pretreatment and posttreatment level in
present processed data was continuous variables with abnormal
distribution. And diverse sample sizes might be another reason.
Therefore, although pooled results indicated that HTS performed a better
effect in increasing CPP, the heterogeneity should be considered.
Except for effect of ICP reduction, option of osmotic therapy should be
made based on safety. Mainly reported adverse events of mannitol
treatment included electrolyte disturbances, hypovolemia, hypotension
and acute kidney injury. For HTS, there were also several common adverse
events included volume overload, severe hypernatremia (>160
mEq/L), acute kidney injury, and the osmotic demyelination syndrome
(26). In present review, some eligible physiological indicators like
MAP, serum sodium, serum osmolarity, HCT and HR were processed for
meta-analyses. As our results indicated, there was no difference in
change of MAP between manitol and HTS groups, and effect of elevation of
serum sodium and serum osmolarity was better in HTS than in mannitol.
Nevertheless, statistic results showed the heterogeneities were extreme
(MAP, I2 = 90%; serum sodium, I2 =
96%; serum osmolarity, I2 = 92%). Moreover, changes
of HCT and HR had no difference in mannitol and HTS groups. And
statistic results show a credible pooled results with no heterogeneity
(HCT, I2 = 15%; HR, I2 = 13%).
Higher serum sodium and serum osmolarity would give a larger osmotic
gradient in HTS group than in mannitol group and this might give an
interpretation that a better efficacy in reduction of ICP in HTS
treatment.
A relationship between hypernatremia and increasing mortality had been
described in a general hospitalized patients in a medical intensive care
unit (27). And in present included trails, the most common cause of
hypernatremia might be iatrogenic, induced by HTS. In a study of HTS
therapy in neurocritically ill patients, authors thought the reason of
the association between hypernatremia and mortality remained unclear,
and an applicable upper threshold for hypernatremia had yet to be
determined (28). They also thought that hypernatremia as a reflection of
treatment with osmotic agents could be a marker of more severe
underlying cerebral injury. Therefore, if an appropriate threshold for
serum sodium and osmolarity are made, high level of serum sodium or
osmolarity should not be reasons that prevent the application of HTS.
Seemingly, patients with hyponatremia should receive HTS treatment.
However, rapid change in serum sodium had been considered as a causative
factor for central pontine myelinolysis, especially in patients with
chronic hyponatremia. Therefore, it should be careful when using HTS in
patients with hyponatremia. On the other hand, hyponatremia and
hyperkalemia were also the most commonly reported electrolyte
abnormalities in mannitol therapy. However, in present meta-analysis of
serum sodium, all seven eligible trials did not report any adverse
effect about hyponatremia. And for hyperkalemia, there were insufficient
data to undergo a meta-analysis. Otherwise, mannitol seemed to have a
higher likehood of acute renal insufficiency than HTS. However, in
included studies, only one study reported detailed data on blood urea
nitrogen, whose results demonstrated no significant difference between
HTS and mannitol (6). As a subgroup analysis, there was no sufficient
studies. If a further research would be performed, it needs another
analysis which renew a specialized subject, so that more eligible trails
might be included.
Except for increasing ICP and CPP, lots of studies indicated that
mannitol and HTS had other favorable and adverse characteristics which
might determine their utilities. As a classical osmotic agent, there was
concern about mannitol because of the diuretic effect, which limited its
application in patients with systematic hypotension. Moreover, a study
indicated that mannitol could increase CBF by inducing blood dilution to
decrease viscosity and causing cerebral vasoconstriction (29). Some
researchers considered that mannitol had a favorable safety profile
although it could cause electrolyte abnormality and renal impairment
(30). Different from mannitol, HTS solutions might be preferred in
situations requiring rapid cardiovascular resuscitation of associated
hemorrhagic shock and arterial hypotension, given the volume expansion
and lack of a diuretic effect (31). It was also indicated that compared
with mannitol there was no pressure rebound in HTS treatment (32). And
HTS could be combined with agents such as dextran or hydroxyethyl
starch, which could prolong the circulatory effect of hypertonicity
(33). Moreover a research demonstrated that not only reduction of ICP
and elevation of CPP, but also improvement of brain tissue oxygen
tension (PbtO2) were reported in HTS treatment (34). In addition,
several studies indicated that HTS was more effective than mannitol in
treatment of refractory intracranial hypertension (34-36). Generally
speaking, although a promising trend of HTS treatment in patient with
elevated ICP is emerging, precise medicine based on characteristics of
mannitol and HTS in different patients would be preferred.
In this study, it was not reported pooled neurological outcomes or
mortality. Because diseases in ten trials were not consistent and there
was no preferable comparability. And two previous meta-analyses reported
the pooled results of neurological outcomes and mortality in patients
with TBI (22, 24). Both of them demonstrated that there was no
significant difference between HTS or mannitol therapies for the
outcomes of neurological function and mortality. In consideration of
lacking new interested data of neurological outcome and mortality, we
did not report this repetitive work in this article.
Nevertheless, our study have several limitations. First, this analysis
has limited number of eligible studies which likely suffers from a small
study effect and low number of events, because of several strict
inclusions. And several trails which preferred HTS treatment, are
excluded because of lacking exact ICP values. In these trails, number of
ICP treatment failure or success was used as primary outcomes. However,
this definition of ICP treatment in different trails were ambiguous and
inconsistent. Therefore, for reducing heterogeneity, we selected
eligible trails which could offer exact quantitative value of ICP.
Second, in all included trails, there were several different
concentrations of HTS. Moreover there were inconsistent conclusions
about whether different concentrations of HTS might have different
effects in reduction of ICP or not (37-39). Consequently, the optimal
HTS concentration is still not unsettled. And the contradictory
conclusions and limitations of traditional meta-analysis suggests that
the direct and indirect comparison principle of network meta-analysis
may be the most appropriate method to explore the best hypertonic agent
for treatment of patients with elevated ICP. In addition, in data
processing part, median and range values or IQR values in some included
studies were transformed into mean and SD values by certain
transformation rules. Theoretically speaking, this transformation is
reasonable, however, it might bring some confounders and generate biases
and errors. For making up it, sensitivity analysis was performed.
Fortunately, results were stable and credible. All of the above may lead
to bias to our results.
Conclusions
Our study indicated HTS had a better efficiency in reduction of elevated
ICP than mannitol in earlier stage. Based on the current level of
evidence related to control of ICP and effect in other physiological
indicators, HTS could be recommended as a first-line agent for managing
patients with elevated ICP. Nevertheless, more RCTs with high quality
are needed to consolidate this recommendation.