Key-words:
Craniotomy - glioma - hypertonic saline - intracranial pressure - mannitol
Introduction
Brain edema remains a major challenge in patients undergoing surgery for supratentorial
intraparenchymal brain tumors causing difficulties in cortical and subcortical dissection
and more parenchymal damage due to brain retraction and ultimately worsening of the
final neurological outcome of the patients. Pretreatment with osmotic fluids is one
of the main tools to prevent acute brain swelling after dural opening during surgery
and to control intracranial pressure (ICP) during the operation.[[1]],[[2]] Mannitol is a well-known osmotic agent for the reduction of ICP through plasma
expansion and decreasing extravascular volume.[[3]]
Nevertheless, the administration of mannitol has certain side effects such as rebound
increase in ICP, electrolyte imbalance, and intravascular volume depletion. Many studies
have searched for alternative hypertonic solutions with different concentrations for
brain relaxation in neurosurgery, of which the hypertonic saline (HS) is the most
popular one.[[4]],[[5]] The administration of HS initially decreases hematocrit and blood viscosity and
increases cerebral perfusion, and eventually, it results in the reduction of ICP and
brain's blood volume and finally leads to brain relaxation.[[3]] In addition to the mentioned properties of HS, it appears to have anti-inflammatory
and neuroprotective effects, which has been studied in several studies in recent years.[[6]],[[7]],[[8]],[[9]]
In recent years, researchers tend to measure specific neural biomarkers to estimate
the intensity of brain injury in patients suffering from brain pathologies. S100B
is a known marker of neural cell damage which is specific to brain injury.[[10]] Serum levels of this biomarker have been shown to increase among patients with
brain tumor and traumatic brain injury, and it has been reported to correlate with
cerebral perfusion pressure and neural integrity.[[11]],[[12]]
Although many studies have evaluated HS for the management of raised ICP (RICP) in
patients with acute and chronic RICP in the intensive care unit (ICU),[[13]],[[14]],[[15]],[[16]] only a few studies have evaluated the effectiveness of HS in brain relaxation of
the patients undergoing elective surgery for brain tumors. This study was to compare
the intraoperative findings and early postoperative outcomes of the patients with
primary supratentorial low-grade gliomas receiving HS with those receiving mannitol
as a well-established osmotic agent.
Materials and Methods
Sixty candidates of elective craniotomy for suspected frontotemporal low-grade glioma
between 18 and 65 years of age were enrolled. Written informed consent was obtained
from all participants, and the institutional review board confirmed the ethical aspects
of the study. Patients with previous neuropsychiatric diseases or cranial operation
for any reason, radiation therapy, treatment with chemotherapeutic and/or immunosuppressive
agents, chronic systemic diseases (renal, hepatic, cardiopulmonary, poorly controlled
diabetes mellitus, and cancer), and/or coagulopathy were excluded from the study.
This was a prospective, randomized, double-blinded study. Patients were randomly allocated
by the department of anesthesiology, by use of computer-generated random number tables,
into one of two treatment groups. Mannitol group received 1 g/kg of mannitol (20%)
and the HS group received 3 ml/kg of HS 5%.
The patients successively received either HS or mannitol to reduce ICP just after
anesthesia induction and before initiation of the surgery. The tumor location and
size was measured on FLAIR sequences of the preoperative brain MRI.
Anesthesia was performed for all patients using the same method, and the same intraoperative
monitoring methods were applied for all of them; injecting fentanyl 1.0 μg/kg, midazolam
0.05 mg/kg, thiopental sodium 4.0 mg/kg, atracurium 0.5 mg/kg, and lidocaine 1.0 mg/kg.
Maintenance of anesthesia was done using continuous infusion of propofol (80–100 μg/kg/min)
and remifentanyl (0.1–0.2 μg/kg/min) and adjusted to maintain the hemodynamic parameters
at last 30% less than preoperative baseline values to decrease intraoperative bleeding.
Patients in the mannitol group received 1 g/kg of mannitol (20%), whereas in the HS
group, 3 ml/kg of HS 5% was administered. Deliberate hypotension was induced in all
patients to limit surgical bleeding using a combination of labetalol and TNG drip
in a similar manner by the anesthesia team who were blinded to the study protocol.
All patients were operated by the same neurosurgical team through pterional approach,
and the same craniotomy free bone flap was cut for all patients. Dural tension score
was reported immediately after the skull opening by the main surgeon who was blinded
to the groups: Grade I, normal dural tension, it was easy for the neurosurgeon to
open the dura mater. Grade II, increased dural tension, the dura mater could be opened
without additional procedures to lower the ICP. Grade III, markedly increased dural
tension, it was necessary to apply additional procedures of lowering the ICP such
as hyperventilation in order to open the dura mater.[[17]]
The primary outcomes of this study were the severity of intraoperative brain edema
during surgery and the postoperative course of the patients during their hospital
stay. During the immediate postoperative period, the “postoperative confusion period”
was defined as the interval between discharge from the recovery room and restoration
of full consciousness in the ICU and was documented by the neurosurgeon. Serum concentrations
of S100B were used as a surrogate objective marker of neuroprotection. To measure
S100B levels, two blood samples were obtained from the patients, the first one 2 h
before the surgery and the second one 48 h after surgery, both stored at −70°C for
the following measurement procedure. Based on intraoperative observation, the extent
of brain edema was classified as low, moderate, or high by a blinded experienced neurosurgeon,
immediately after dural opening and before cerebrospinal fluid (CSF) drainage. Furthermore,
the amounts of intraoperative blood loss and urine volume during surgery were documented
as the secondary outcomes.
Serum concentrations of S100B were measured by BioVendor GmbH, based on the enzyme-linked
immunosorbent assay method and expressed in microgram/liter unit.
Statistical analysis
Statistical analysis was performed using the SPSS (IBM SPSS Statistics for Windows,
Version 24.0. Armonk, NY, USA: IBM Corp; 2016). The confidence level of at least 95%
or maximum error of 5% (P < 0.05) has been selected as the level of significance.
The normality assumption test was carried out by the Kolmogorov–Smirnov test. Student's
t-test, Chi-square, and 2-way ANOVA with repeated measure ANOVA were used to compare
the main outcomes between the two groups.
Discussion
We compared the effects of 20% mannitol with those of 3% HS on the change in ICP among
patients undergoing surgery for supratentorial tumors. Both hyperosmolar solutions
produced significant decreases in ICP from the baseline.
In the clinical practice, the ICP is not routinely measured during elective neurosurgical
procedures, and neurosurgeons evaluate the tension of the dura mater based on their
experience before opening the dura mater. If the tension of the dura mater is estimated
to be high, brain tissue might protrude through the craniotomy site, which increases
the risk of cerebral ischemia with possible worsening of the neurological outcome.
Therefore, the dural tension score estimated by the senior surgeon after craniotomy
has been shown to be strongly correlated with the degree of cerebral edema and ICP.[[18]]
Osmotic agents have been used to control RICP since many years ago, however mannitol
as the classic osmotic agent in the literature of neurosurgery has important side
effects such as volume depletion and electrolyte imbalance that may hinder its application
in many clinical conditions. HS has been promising as an osmotic agent to control
RICP, especially among patients with traumatic brain injury. Infusion of HS creates
an osmotic force that draws the fluid back into the interstitial and intravascular
area from the intracellular area due to the impermeability of the blood–brain barrier
to sodium.[[19]] In addition, HS also decreases the formation and/or enhances the reabsorption of
the CSF.[[20]] In an animal model, Toung et al. examined the effect of HS on cerebral edema due
to tumor. They found that HS was more effective than mannitol in reducing both ipsilateral
and contralateral hemispheric water content as measured by wet-to-dry weight ratios.[[21]] In clinical studies, HS has also been shown to reduce ICP in different intracranial
diseases, particularly in head trauma with increased ICP.[[22]],[[23]] It has been proposed that HS remains effective in intracranial hypertension refractory
to treatment with mannitol.[[24]]
Our study included a relatively homogenous group of the patients in terms of pathology
(low-grade astrocytoma) and location (frontotemporal) to compare the effectiveness
of HS versus mannitol in achieving brain relaxation during elective craniotomy. The
severity of the brain edema reported by the surgeon did not have a significant difference
between the two groups (severe edema reported in six patients in mannitol and five
in HS group, P: 0.729), and our data show that HS is at least as effective as mannitol
in terms of controlling brain edema during surgery.
Although all hyperosmolar agents cause diuresis, the amount of urinary output during
surgery was significantly lower in the HS group (609 ml in HS and 725 ml in the mannitol
group, P: 0.001), whereas the dosage of other intraoperative anti-edema therapies
(furosemide and hyperventilation) did not differ significantly among the two groups
(applied in 19 and 16 patients in mannitol and HS groups, respectively, P: 0.28).
This finding may result from the stimulation of natriuretic peptide (ANP) release
by HS and not merely a direct osmotic diuresis, which might assist in avoiding hypovolemia
and hypotension.[[18]]
We also observed that the duration of the postoperative confusion and the period of
corticosteroid therapy for postoperative brain edema were significantly shorter in
the HS than the mannitol group (3.8 h vs. 5.3 h, P: 0.003 and 3.4 days vs. 5.2 days,
P: 0.03). The length of ICU stay was shorter in the HS group (16.3 vs. 27.9 h, P:
0.04); however, the total length of hospital stay did not differ significantly among
the two groups (6.3 days in mannitol group and 5.8 days in the HS group, P: 0.53).
All of these findings may not completely be explained just on the basis of the osmotic
effects of the HS and considering the well-known immune modulatory effects of HS;[[6]],[[8]],[[9]] there may be a neuroprotective role beyond its circulatory benefits. Although it
is still considered a research tool rather than a valid clinical measurement, Vos
et al. have suggested that the S100B is a known inflammatory factor specific to brain
injury which increases in brain tumor patients.[[10]] The range of S100B blood level is between 0.02 and 0.05 μg/l in normal individuals
and 0.19 μg/l in patients with brain tumor and increased to 1.07 μg/l after tumor
resection in one study.[[11]] The uniform rise in postoperative serum S100B levels seen in our patients also
supports the role of S100B as a marker of neural damage and/or inflammation. Although
the serum levels of S100B before surgery in both groups were similar, the amount of
rise in S100B level was significantly lower in patients who received HS in contrast
to those who received mannitol (0.484 ± 0.153 μg/L vs. 0.851 ± 0. 058 μg/L, P: 0.001)
[[Figure 1]]. Usui et al. reported that S100B is excreted and eliminated completely through
the kidneys.[[25]] Considering the significantly higher urine volume in the mannitol group, one may
expect lower S100B levels in these patients, while our data show higher serum S100B
levels in this group despite their higher urinary outputs. Nevertheless, S100B has
been used only as an ancillary objective measurement in this study, and deriving a
clear conclusion regarding the relation between S100B and the clinical outcome of
the patients receiving HS before surgical resection of brain tumors is not possible
from this study.
Limitations
One major shortcoming of our study was the lack of direct measurement of cerebral
perfusion and rheological properties of blood. In addition, the potential long-term
beneficial effects of the HS on the neurological outcome of the patients remain to
be evaluated. We suggest that anti-inflammatory and neuroprotective effects of HS
be further studied in addition to its brain relaxation and circulatory features. There
remain other aspects of HS to be evaluated by further studies, such as its effect
on the coagulation pathways and platelet function.
Conclusion
In summary, the administration of HS seems to be safe and effective in achieving brain
relaxation needed for elective craniotomies to resect intra-axial brain tumors and
at the same time may have additional benefits by improving neuroprotection during
the neurosurgical procedures.
