CliniCal artiCle
A prospective randomized trial of the optimal dose of
mannitol for intraoperative brain relaxation in patients
undergoing craniotomy for supratentorial brain tumor
resection
hyungseok seo, MD, PhD,1 eugene Kim, MD,2 haesun Jung, MD,1 Young-Jin lim, MD, PhD,1
Jin wook Kim, MD, PhD,3 Chul-Kee Park, MD, PhD,3 Young-bem se, MD,3
Young-tae Jeon, MD, PhD,4 Jung-won hwang, MD, PhD,4 and hee-Pyoung Park, MD, PhD4
Departments of 1Anesthesiology and Pain Medicine and 3Neurosurgery, Seoul National University Hospital, Seoul National
University College of Medicine, Jongno-gu, Seoul; 2Department of Anesthesiology and Pain Medicine, Daegu Catholic University
Medical Center, School of Medicine, Catholic University of Daegu; and 4Department of Anesthesiology and Pain Medicine, Seoul
National University Bundang Hospital, Seoul National University College of Medicine, Bundang-gu, Seongnam, Korea
obJeCtive Mannitol is used intraoperatively to induce brain relaxation in patients undergoing supratentorial brain
tumor resection. The authors sought to determine the dose of mannitol that provides adequate brain relaxation with the
fewest adverse effects.
MethoDs A total of 124 patients were randomized to receive mannitol at 0.25 g/kg (Group A), 0.5 g/kg (Group B), 1.0
g/kg (Group C), and 1.5 g/kg (Group D). The degree of brain relaxation was classified according to a 4-point scale (1,
bulging; 2, firm; 3, adequate; and 4, perfectly relaxed) by neurosurgeons; Classes 3 and 4 were considered to indicate
satisfactory brain relaxation. The osmolality gap (OG) and serum electrolytes were measured before and after mannitol
administration.
resUlts The brain relaxation score showed an increasing trend in patients receiving higher doses of mannitol (p =
0.005). The incidence of satisfactory brain relaxation was higher in Groups C and D than in Group A (67.7% and 64.5%
vs 32.2%, p = 0.011 and 0.022, respectively). The incidence of OG greater than 10 mOsm/kg was also higher in Groups
C and D than in Group A (100.0% in both groups vs 77.4%, p = 0.011 for both). The incidence of moderate hyponatremia
(125 mmol/L ≤ Na+ < 130 mmol/L) was significantly higher in Group D than in other groups (38.7% vs 0.0%, 9.7%, and
12.9% in Groups A, B, and C; p < 0.001, p = 0.008, and p = 0.020, respectively). Hyperkalemia (K+ > 5.0 mmol/L) was
observed in 12.9% of patients in Group D only.
ConClUsions The higher doses of mannitol provided better brain relaxation but were associated with more adverse
effects. Considering the balance between the benefits and risks of mannitol, the authors suggest the use of 1.0 g/kg of
intraoperative mannitol for satisfactory brain relaxation with the fewest adverse effects.
Clinical trial registration no.: NCT02168075 (clinicaltrials.gov)
http://thejns.org/doi/abs/10.3171/2016.6.JNS16537
KeY worDs brain tumor; brain relaxation; mannitol; hyponatremia; osmolality gap; oncology
M
ANNITOL is widely used to reduce intracranial
pressure (ICP) in patients with cerebral edema.2
Mannitol reduces ICP by decreasing brain water content, improving cerebral microcirculation, reducing
cerebral blood flow via vasoconstriction, and decreasing
cerebrospinal fluid volume.11 However, mannitol has several adverse effects, including hypochloremic metabolic
alkalosis associated with volume contraction and diuresis,
hypernatremia, hypokalemia, and renal failure.11
Because of tumor size, brain edema, or increased ICP,
satisfactory brain relaxation can be required before tumor
resection.10 Satisfactory brain relaxation improves the surgical approach in patients undergoing craniotomy.1 Mannitol is generally administered intravenously at doses be-
abbreviations ICP = intracranial pressure; OG = osmolality gap.
sUbMitteD March 2, 2016. aCCePteD June 8, 2016.
inClUDe when Citing Published online August 19, 2016; DOI: 10.3171/2016.6.JNS16537.
©AANS, 2016
J neurosurg August 19, 2016
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h. seo et al.
tween 0.25 and 1.5 g/kg,3,9 but the optimal dose has not
been established. A previous meta-analysis found a weak
linear relationship between mannitol dose and change in
ICP.13 In contrast, another study found a dose-response effect of mannitol with ICP reduction in patients who had
sustained traumatic brain injury;14 however, the mannitol
doses (50 and 100 g) were not standardized based on body
weight. Although the dose-response relationship between
mannitol and intraoperative brain relaxation was investigated in a previous study conducted by Quentin and colleagues,9 the proportion of patients with midline shift on
brain CT, which is an important sign of increased ICP,
was not balanced across treatment arms in their study.
The authors showed no difference in brain relaxation score
between the high-dose (1.4 g/kg) and low-dose (0.7 g/kg)
mannitol groups. However, after adjustment for the presence of midline shift, the high-dose mannitol group had
a better brain relaxation score than the low-dose mannitol
group.
We hypothesized that mannitol has a dose-related effect on brain relaxation. In the present study, we prospectively assessed the effect of different doses of mannitol
on intraoperative brain relaxation and adverse effects in
patients undergoing craniotomy for the removal of supratentorial brain tumors. We also sought to determine the
mannitol dose to provide adequate brain relaxation with
the fewest adverse effects.
Methods
A total of 124 adult patients (age range 20–80 years)
scheduled for craniotomy for supratentorial brain tumor
resection under general anesthesia at Seoul National University Hospital were enrolled in the study between June
2014 and May 2015. All patients harbored a unilateral lesion and showed a midline shift (> 3 mm) on brain MRI,
which was determined by a blinded radiologist. The protocol for our prospective randomized study was registered
at clinicaltrials.gov (NCT02168075). The institutional
review board approved our study, and written informed
consent was obtained from all participants.
exclusion Criteria
Patients with an American Society of Anesthesiologists
Physical Status Score ≥ IV, Glasgow Coma Scale < 13, severe hyponatremia or hypernatremia (Na+ < 120 mmol/L
or > 155 mmol/L, respectively), cardiac dysfunction (i.e.,
congestive heart failure, left ventricle ejection fraction <
40%), renal dysfunction (glomerular filtration rate < 60
ml/min/1.73 m2), or preoperative mannitol use were excluded from the study. Furthermore, patients who had undergone extraventricular drainage or ventriculoperitoneal
shunt treatment were also excluded.
randomization and group assignments
The randomization sequence was generated by an anesthesiologist blinded to this study before the patients were
enrolled. Randomization was performed in blocks of 4 or 8
patients using randomization software. Patients were randomly assigned to one of 4 groups (allocation ratio 1:1:1:1)
according to the dose of mannitol administered: 0.25 g/kg
(Group A), 0.5 g/kg (Group B), 1.0 g/kg (Group C), and 1.5
2
J neurosurg August 19, 2016
g/kg (Group D). The mannitol dose was calculated using a
patient’s total body weight, and the participating surgeons
were blinded to dose.
anesthesia induction and Maintenance
No patient received medication preoperatively. After
arriving at the operating room, the patient was monitored
using noninvasive blood pressure, pulse oxygen saturation, and electrocardiogram measurements. Anesthesia
was induced using remifentanil (effect-site concentration, 4.0 ng/ml) and propofol (effect-site concentration,
4.0 μg/ml) continuous infusion using a target-controlled
infusion device (Orchestra Bass Primera, Fresenius Kabi)
and preoxygenation with 100% oxygen via a facial mask.
Rocuronium (0.6 mg/kg) was administered to facilitate
tracheal intubation, and then a radial artery was catheterized to directly monitor continuous arterial pressure. After intubation, an esophageal stethoscope (DeRoyal) was
placed in the esophagus to monitor core temperature. Both
lungs were mechanically ventilated with a 50% oxygen–
air mixture, and total fresh gas flow was maintained at 2
L/min throughout surgery. Tidal volume and respiratory
rate were adjusted to maintain arterial carbon dioxide partial pressure between 35 and 40 mm Hg. No positive endexpiratory pressure was applied in this setting.
All patients were in the supine or supine-lateral position without severe neck flexion, extension, or rotation.
The confluence of sinuses was positioned higher than the
heart level in all patients.
During surgery, anesthesia was maintained by continuous infusion of propofol and remifentanil. During surgery, the propofol and remifentanil doses were adjusted to
maintain a mean blood pressure within 20% of baseline.
Mannitol administration and outcome Measurement
The primary end point was the trend in proportions of
satisfactory brain relaxation. A predetermined amount of
20% mannitol by each corresponding group was intravenously administered over 15–20 minutes at the time of
skin incision. Three neurosurgeons participated in the
present study, and one of them rated each case. In other
words, 3 neurosurgeons who were blinded to the mannitol
dose assessed the degree of brain relaxation immediately
after opening the dura. The assessment was performed using a 4-point scale, with 1 denoting bulging or the condition that additional methods for brain relaxation are immediately and always required in order to continue the
surgical procedure because of brain swelling; 2, firm or
the condition that additional methods for brain relaxation
are occasionally required to continue the surgical procedure; 3, adequate; and 4, perfectly relaxed. In all patients,
the degree of brain relaxation was assessed at the time of
dural opening and satisfactory brain relaxation was defined as a brain relaxation score of 3 or 4. If neurosurgeons
required a greater degree of brain relaxation in patients
without satisfactory brain relaxation at the time of evaluating the degree of brain relaxation, additional methods
such as administration of additional mannitol (0.25 g/kg),
hyperventilation (PaCO2 between 30 and 35 mm Hg), and
the reverse Trendelenburg position were used.
Mannitol dose for intraoperative brain relaxation
Fig. 1. A CONSORT flow diagram.
table 1. Demographics in the 124 patients included in this study
Variables
Group A (n = 31)
Group B (n= 31)
Group C (n = 31)
Group D (n = 31)
p Value
Mean age in yrs (range)
Male sex
Mean height, cm
Mean weight, kg
Mean BMI, kg/m2
Tumor type
Anaplastic astrocytoma
Glioblastoma
Oligodendroglioma
Other glioma
Meningioma
Metastasis
Other
Tumor location
Frontal
Temporal
Parietal
Occipital
Sphenoidal
Other
Mean max tumor diameter, mm
Mean midline shift, mm
Peritumoral edema >10 mm
52.5 (32–74)
20 (64.5%)
165.5 (9.4)
65.0 (10.0)
23.5 (2.5)
53.1 (28–78)
15 (48.4%)
162.7 (8.9)
65.7 (12.8)
24.9 (4.4)
52.1 (23–79)
12 (38.7%)
162.4 (7.9)
63.6 (10.0)
23.9 (3.9)
48.9 (24–76)
14 (45.2%)
163.2 (9.5)
64.0 (13.0)
23.9 (3.9)
0.474
0.214
0.508
0.723
0.447
0.868
0 (0%)
5 (16.1%)
1 (3.2%)
3 (9.6%)
16 (51.6%)
3 (9.6%)
3 (9.6%)
2 (6.4%)
6 (19.2%)
3 (9.6%)
3 (9.6%)
10 (32.2%)
5 (16.1%)
2 (6.4%)
1 (3.2%)
5 (16.1%)
2 (6.4%)
1 (3.2%)
14 (45.2%)
4 (12.9%)
4 (12.9%)
4 (12.9%)
6 (19.2%)
1 (3.2%)
3 (9.6%)
12 (38.7%)
2 (6.4%)
3 (9.6%)
0.932
21 (67.7%)
4 (12.9%)
2 (6.4%)
1 (3.2%)
1 (3.2%)
2 (6.4%)
50.6 (14.4)
9.2 (4.3)
24 (77.4%)
16 (51.6%)
4 (12.9%)
5 (16.1%)
1 (3.2%)
3 (9.6%)
2 (6.4%)
45.5 (15.4)
10.0 (6.7)
25 (80.6%)
16 (51.6%)
6 (19.2%)
4 (12.9%)
2 (6.4%)
1 (3.2%)
2 (6.4%)
50.0 (16.2)
8.4 (5.9)
25 (80.6%)
18 (58.1%)
3 (9.6%)
4 (12.9%)
2 (6.4%)
1 (3.2%)
3 (9.6%)
50.7 (11.8)
9.0 (4.0)
27 (87.1%)
0.476
0.695
0.879
The administered dose of mannitol is 0.25 g/kg in Group A, 0.5 g/kg in Group B, 1.0 g/kg in Group C, and 1.5 g/kg in Group D. Values are
presented as the number of patients (%) unless indicated otherwise. Mean values are presented as the mean (SD) unless indicated otherwise.
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h. seo et al.
Laboratory data, including electrolytes and serum osmolality, were recorded at 4 specific time points: immediately before mannitol administration, and at 30, 60, and
180 minutes after the end of mannitol administration. Because mannitol shows a peak effect 30 minutes after administration, the correlation between the degree of brain
relaxation and serum osmolality level at this time point
was investigated. The osmolality gap (OG) was calculated
as serum osmolality - calculated osmolality (2 × [Na+,
mmol/L] + [glucose, mg/dl]/18 + [BUN, mg/dl]/2.8). OG
> 10 mOsm/kg was considered high.
Radiographic parameters were analyzed on brain MR
images using a picture archiving and communication system (PACS; M-view, version 5.4; Infinitt Healthcare). The
maximal intersecting diameter of the mass was measured
using T1-weighted enhanced images for contrast-enhancing tumors or T2-weighted images for contrast nonenhancing tumors. Peritumoral edema was assessed using
measurement of the shortest straight line between the tumor margin and the far point of peritumoral edema on
FLAIR images. The degree of midline shift was defined
by the maximal distance from the imaginary midline of
brain to the deviated septum pellucidum.
statistical analysis
A previous study found that the incidence of satisfactory brain relaxation was 70% after administration of a
1.0-g/kg dose and 55% after a 0.7-g/kg dose of mannitol.9 Assuming 40%, 50%, 70%, and 80% incidences of
satisfactory brain relaxation in Groups A, B, C, and D,
respectively, and assuming a Type 1 error rate of 0.05 and
power of 80%, we calculated that at least 26 patients were
required for each group by the Cochrane-Armitage test
for linear trend in proportions. Furthermore, assuming a
dropout rate of 20%, a total of 124 patients were needed
for the study. The data were screened for normality using
the Shapiro-Wilk test. Continuous variables with normal
distribution were compared using ANOVA with Bonferroni correction, while continuous variables without normal distribution were compared using the Kruskal-Wallis
test, followed by the Mann-Whitney U-test. The chisquare test or Fisher’s exact test was used for categorical
data analysis. The correlation between mannitol dose and
degree of brain relaxation was evaluated using the linearby-linear association chi-square test. The laboratory data
were compared using a repeat-measure ANOVA, followed
by an ANOVA with Bonferroni correction at each time
point. A p value < 0.05 was deemed to indicate statistical
significance.
results
The study included 124 patients (Fig. 1). The demographic data were comparable among groups (Table 1).
There was an increasing trend in the brain relaxation
score in patients receiving high-dose mannitol (p = 0.005).
The incidence of satisfactory brain relaxation was significantly higher in Groups C and D than in Group A (67.7%
and 64.5% vs 32.3%, p = 0.011 and 0.022, respectively;
Fig. 2), but not in Group B (51.6%). The overall incidence
of additional methods for further brain relaxation was
4
J neurosurg August 19, 2016
Fig. 2. Proportions of the degree of brain relaxation in each group. The
administered dose of mannitol is 0.25 g/kg in Group A, 0.5 g/kg in Group
B, 1.0 g/kg in Group C, and 1.5 g/kg in Group D. The proportion of
satisfactory brain relaxation (showing “perfectly relaxed” or “adequate”
degree of brain relaxation) is 32.3%, 51.6%, 67.7%, and 64.5% in
Groups A, B, C, and D, respectively. There is an increasing trend in the
proportion of satisfactory brain relaxation in patients receiving high-dose
mannitol (p = 0.005).
comparable among the 4 groups (Table 2). There was a
significant correlation between the degree of brain relaxation and serum osmolality at 30 minutes after the end of
mannitol administration (correlation coefficient 1.43, p =
0.036).
Serum osmolality (median [IQR]) measured at 30 minutes after the end of mannitol administration was significantly higher in Group D than in other groups (315 [310–
317] vs 303 [301–309], 303 [300–307], and 306 [303–310]
mOsm/kg in Groups A, B, and C, p < 0.001, respectively)
and was higher in Group C than in Group B (p = 0.008,
Table 2).
The mean OG peaked at 30 minutes after the end of
mannitol administration and then gradually decreased
in all groups (Fig. 3). The OG (mean [SD]) at this time
point was significantly higher in Group D than in the other
groups (38 [5] vs 13 [6], 18 [5], and 25 [8] mOsm/kg in
Groups A, B, and C, p < 0.001, respectively). The incidence of a high OG (OG > 10 mOsm/kg) was higher in
Groups C and D than in Group A (100.0% in both groups
vs 77.4%, p = 0.011 for both; Table 3). The serum sodium
concentration (mean [SD]) in Group A was higher than
that of all other groups at this time point (138 [3] vs 135
[4], 134 [3], and 131 [4] mmol/L in Groups B, C, and D;
p = 0.014, p < 0.001, and p < 0.001, respectively). The in-
Mannitol dose for intraoperative brain relaxation
table 2. intraoperative data and postoperative outcomes
Variables
Intraop data
Mean time to assess brain relaxation from
end of mannitol administration, mins
Median op time, mins
Median anesthesia time, mins
Median administered fluids, ml
Median total urine output, ml
Median total estimated blood loss, ml
Median total fluid balance, ml
Median serum osmolality after mannitol
administration, mOsm/kg
At T1
At T2
At T3
At T4
Additional methods for brain relaxation
Overall
Additional mannitol administration
Transient hyperventilation
Transient hyperventilation + additional mannitol administration
Reverse Trendelenburg position
Postop outcome
Median ICU stay, days
Median hospital stay, days
Group A (n = 31)
33 (5)
Group B (n = 31)
32 (6)
Group C (n = 31)
32 (5)
Group D (n = 31)
35 (6)
269 [199–341]
330 [294–415]
2250 [1575–2825]
1540 [725–1908]
600 [300–800]
520 [28–912]
258 [239–377]
330 [320–458]
1800 [1700–2400]
1145 [910–1545]
540 [288–850]
330 [−40 to 833]
263 [235–349]
340 [305–420]
2300 [1500–2850]
1500 [1180–2500]†
500 [350–700]
−70 [−300 to 945]
323 [235 –391]
390 [300–474]
2225 [1575–2913]
2195 [1394–3005]†,‡
650 [400–1100]
−175 [−670 to 620]**
299 [295–302]
303 [301–309]
303 [299–308]
303 [300–306]
298 [295–304]
303 [300–307]
303 [299–306]
299 [295–307]
295 [291–300]
306 [303–310]†
306 [302–310]††
305 [299–309]
6 (19%)
4 (12.9%)
1 (3.2%)
1 (3.2%)
7 (22.6%)
0 (0%)
2 (6.4%)
4 (12.9%)
3 (9.7%)
0 (0%)
2 (6.4%)
1 (3.2%)
2 (6.4%)
0 (0%)
2 (6.4%)
0 (0%)
0 (0%)
1 (3.2%)
0 (0%)
0 (0%)
2 [2–3]
9 [8–13]
2 [2–3]
9 [8–13]
2 [2–4]
12 [9–16]
3 [2–5]
11 [8–20]
299 [291–303]
315 [310–317]*,†,‡
312 [309–314]*,†,‡
307 [304–313]**,††,‡‡
T1 = just before the mannitol administration; T2 = 30 minutes after the end of mannitol administration; T3 = 60 minutes after the end of mannitol administration; T4 = 180
minutes after the end of mannitol administration.
Values are presented as the number of patients (%) unless indicated otherwise. Mean values are presented as the mean (SD). Median values are presented as the
median [IQR].
*p < 0.01, compared with Group A; **p < 0.05, compared with Group A; †p < 0.01, compared with Group B; ††p < 0.05, compared with Group B; ‡p < 0.01, compared
with Group C; ‡‡p < 0.05, compared with Group C.
cidence of hyponatremia (serum Na+ < 135 mmol/L) was
higher in Group D than in Groups A and B (80.6% vs
25.8% and 45.2%, p < 0.001 and p = 0.004), and the incidence of moderate hyponatremia (125 ≤ serum Na+ < 130
mmol/L) was significantly higher in Group D than in the
other groups (38.7% vs 0.0%, 9.7%, and 12.9% in Groups
A, B, and C; p < 0.001, p = 0.008, and p = 0.020, respectively). The serum potassium level (mean [SD]) was higher
in Group D than in Group A at 30 minutes after the end of
mannitol administration (4.1 [0.5] vs 3.7 [0.3] mmol/L, p
= 0.002) and higher in Group D than in Groups A and B at
60 minutes after the end of mannitol administration (4.2
[0.4] vs 3.9 [0.3] and 3.9 [0.3] mmol/L; p < 0.001 and p =
0.004, respectively).
In this study, 2 patients (1 each from Groups C and D)
received potassium replacement because of hypokalemia.
Otherwise, there was no adverse effect requiring treatment.
Discussion
We found that the incidence of satisfactory brain relaxation increased as the dose of mannitol increased; how-
ever, imbalances in the OG and serum electrolytes also
increased in high-dose mannitol.
Mannitol is widely used to reduce ICP and improve
brain relaxation in patients undergoing brain tumor resection.3,11 When the blood-brain barrier is intact, mannitol
may induce brain relaxation by removing water from brain
tissue or by decreasing cerebral blood flow.11 However,
mannitol has several adverse effects, such as electrolyte
imbalances, volume contraction, and renal failure.8,9 Increased serum osmolality can result in outward movement
of water, leading to extracellular volume expansion, dilutional hyponatremia, and hyperkalemia.8 Thus, when using mannitol, the risk-benefit balance should be carefully
considered.
Several previous studies have shown a relationship between mannitol dose and the degree of ICP reduction.9,13,14
Sorani et al.14 found that a higher dose of mannitol produced a greater reduction in ICP; however, the data were
collected retrospectively in an intensive care unit in patients with traumatic brain injury. Moreover, the 2 fixed
mannitol doses (50 and 100 g) were not adjusted for body
weight, and adverse effects, such as electrolyte imbalance,
J neurosurg August 19, 2016
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h. seo et al.
Fig. 3. Comparison of osmolality gap (a) and sodium (b) and potassium (C) levels at each time point among groups. The time
points are as follows: T1, just before the mannitol administration; T2, 30 minutes after the end of mannitol administration; T3, 60
minutes after the end of mannitol administration; and T4, 180 minutes after the end of mannitol administration. *p < 0.01, compared
with Group A; **p < 0.05, compared with Group A; †p < 0.01, compared with Group B; ††p < 0.05, compared with Group B; ‡p <
0.01, compared with Group C; ‡‡p < 0.05, compared with Group C.
were not investigated. Quentin et al.9 found that a 1.4-g/kg
dose of mannitol resulted in greater brain relaxation than
did a 0.7-g/kg dose. However, the authors did not control
for the number of patients exhibiting a midline shift on the
brain CT or MRI, which is an important sign of increased
ICP. In contrast, our prospective study used 4 incremental
doses of mannitol, and the number of patients with midline
shift was well controlled.
Mannitol administration affects serum osmolality and
causes electrolyte imbalances, such as hyponatremia and
hyperkalemia.17 The OG is an indicator of unmeasured
serum osmoles, such as mannitol, and can be used to
monitor osmolality change with mannitol administration.6 When using mannitol, the OG should be less than
55 mOsm/kg because of its nephrotoxicity.5 We found that
the mean OG was significantly higher in Group D than in
the other groups at all time points, and the maximal OG
was 48 mOsm/kg 30 minutes after mannitol administration. Although we administered 1.5 g/kg of mannitol as
the highest dose in the present study and none of the pa6
J neurosurg August 19, 2016
tients exhibited renal dysfunction, nephrotoxicity must be
taken into consideration in the use of mannitol, particularly when repeat administration of a high dose of mannitol was required. Mannitol can cause a dose-dependent
increase in hyponatremia.15 Similarly, serum sodium levels decreased after the administration of mannitol in this
study. Compared with the other groups, the serum sodium
levels in Group D were significantly lower at 30 and 60
minutes but returned to baseline 180 minutes after the
administration of the drug. Although hyponatremia has
been shown to return to preadministration levels within a
day following a high dose of the drug,15 acute changes in
serum sodium levels may be harmful because rapid-onset
hyponatremia can become symptomatic.16 Hyperkalemia
caused by an increase in intracellular potassium concentration as a result of cellular water loss and subsequent
passive outflow of potassium is another serious adverse
effect of mannitol.4,16 We observed a transient increase
in serum potassium levels after mannitol administration
in all groups. In Group D, the mean potassium level in-
Mannitol dose for intraoperative brain relaxation
table 3. the incidences of electrolyte disturbance and high osmolality gap
Variable
Hyponatremia
Incidence
Severity
Mild (130≤Na+<135 mmol/L)
Moderate (125≤Na+<130 mmol/L)
Hypernatremia
Incidence
Severity
Mild (145<Na+≤150 mmol/L)
Moderate (150<Na+≤170 mmol/L)
Hypokalemia
Incidence
Severity
Mild (3.0≤K+<3.5 mmol/L)
Moderate (2.5≤K+<3.0 mmol/L)
Hyperkalemia
Incidence
Severity
Mild (5.0<K+≤6.0 mmol/L)
Moderate (6.0<K+≤8.0 mmol/L)
High OG (>10 mOsm/kg)
Incidence
Group A (n = 31)
Group B (n = 31)
Group C (n = 31)
8 (25.8%)
14 (45.2%)
19 (61.3%)
25 (80.6%)*,†
8 (25.8%)
0 (0%)
11 (35.5%)
3 (9.7%)
15 (48.4%)
4 (12.9)
13 (41.9%)
12 (38.7%)*,†,‡‡
2 (6.5%)
1 (3.2%)
0 (0%)
0 (0%)
2 (6.5%)
0 (0%)
1 (3.2%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
12 (38.7%)
8 (25.8%)
10 (32.3%)
12 (38.7%)
12 (38.7%)
0 (0%)
7 (22.6%)
1 (3.2%)
9 (29.0%)
1 (3.2%)
11 (35.5%)
1 (3.2%)
0 (0%)
0 (0%)
0 (0%)
4 (12.9%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
4 (12.9%)**,††,‡‡
0 (0%)
24 (77.4%)
30 (96.8%)
31 (100%)**
Group D (n = 31)
31 (100%)**
*p < 0.01, compared with Group A; **p < 0.05, compared with Group A; †p < 0.01, compared with Group B; ††p < 0.05, compared with Group B;
‡p < 0.01, compared with Group C; ‡‡p < 0.05, compared with Group C.
creased by more than 15% of baseline 60 minutes after
the drug was administered. Although potassium levels
returned to the preadministration level after 180 minutes,
intraoperative hyperkalemia may cause cardiac dysfunction.7,12 Although mannitol may cause hypokalemia as a
result of volume contraction due to osmotic diuresis,8,11
mild hypokalemia can be ameliorated with appropriate
volume replacement and thus may be less clinically significant than hyperkalemia.11
We found a positive correlation between increased
brain relaxation and mannitol dose. The incidence of satisfactory brain relaxation was significantly greater at higher
doses of mannitol (1.0 and 1.5 g/kg) compared with the
lowest dose (0.25 g/kg). However, the incidence of adverse
effects also increased according to drug dose. The incidence of hyponatremia, particularly moderate hyponatremia, was significantly higher at the 1.5-g/kg than at the
1.0-g/kg dose. Moreover, the increases in the serum osmolality and OG were more marked at the 1.5-g/kg than at
the 1.0-g/kg dose, and the serum potassium concentration
was significantly higher in the 1.5-g/kg dose group than in
the other groups. Our results showed that although a 0.25g/kg dose of mannitol caused minimal electrolyte disturbance, the incidence of satisfactory brain relaxation was
low compared with that using higher doses. Conversely,
the 1.5-g/kg dose of mannitol produced the highest degree
of brain relaxation but was associated with the highest incidence of electrolyte imbalance. Based on our results, the
1.0-g/kg dose of mannitol can be regarded as the optimal
dose producing the highest degree of brain relaxation with
the fewest adverse effects.
Our study has some limitations. First, the mannitol dose
was not perfectly blinded in this study, because the attending anesthesiologists knew the dose, although the 3 neurosurgeons who assessed the brain relaxation were completely blinded to the mannitol dose. Second, although the
degree of brain relaxation was evaluated by neurosurgeons
blinded to the mannitol dose using a 4-point scale,9 this
method is subjective. Quantitative measurements of ICP,
such as ventricular or lumbar cerebrospinal fluid drainage,
may provide more objective results; however, the methodology is associated with risks such as bleeding and infection. Third, we did not quantitatively measure the extent of
peritumoral brain edema. Given the capacity of mannitol
to transfer water from brain tissue to plasma, it may be
helpful to investigate the relationship between the degree
of peritumoral brain edema and mannitol effect.
Conclusions
This study showed that the higher doses of mannitol provided better brain relaxation but were associated with more
anticipated adverse effects. Therefore, when using mannitol
in clinical practice, the balance between benefits and risks
should be considered. This study suggests that 1.0 g/kg of
mannitol may be the optimal dose for satisfactory brain relaxation with the fewest complications in patients undergoing craniotomy for supratentorial brain tumor removal.
J neurosurg August 19, 2016
7
h. seo et al.
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Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this
paper.
author Contributions
Conception and design: HP Park, Seo, E Kim, Jeon. Acquisition
of data: HP Park, Seo, E Kim, Jung, JW Kim, CK Park, Se. Analysis and interpretation of data: HP Park, Seo, Lim, CK Park, Se,
Hwang. Drafting the article: Seo. Critically revising the article:
HP Park, Lim, JW Kim, Jeon, Hwang. Reviewed submitted version of manuscript: HP Park. Approved the final version of the
manuscript on behalf of all authors: HP Park. Statistical analysis:
Seo. Administrative/technical/material support: E Kim, Jung.
Study supervision: HP Park.
Correspondence
Hee-Pyoung Park, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul
03080, Korea. email: [email protected].