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Agreement of measured and calculated serum osmolality during the infusion of mannitol or hypertonic saline in patients after craniotomy: a prospective, double-blinded, randomised controlled trial

  • Qian Li1,
  • Han Chen1,
  • Jing-Jing Hao1,
  • Ning-Ning Yin1,
  • Ming Xu1 and
  • Jian-Xin Zhou1Email author
BMC Anesthesiology201515:138

https://doi.org/10.1186/s12871-015-0119-4

Received: 2 March 2015

Accepted: 2 October 2015

Published: 7 October 2015

Abstract

Background

Mannitol and hypertonic saline are used to ameliorate brain edema and intracranial hypertension during and after craniotomy. We hypothesized that the agreement of measured and calculated serum osmolality during the infusion of hypertonic saline would be better than mannitol. The objective was to determine the accuracy of serum osmolality estimation by different formulas during the administration of hyperosmolar agent.

Methods

A prospective, randomized, double-blinded, controlled trial was conducted in a 30-bed neurosurgical intensive care unit at a university hospital. Thirty-five adult patients requiring the use of hyperosmolar agents for prevention or treatment of brain edema after elective craniotomy were enrolled, and randomly assigned 1:1 to receive 125 mL of either 20 % mannitol (mannitol group) or 3.1 % sodium chloride solution (hypertonic saline group) in 15 min. Serum osmolality, serum sodium and potassium concentration, blood urea nitrogen and blood glucose concentration were measured during the study period. The primary outcome was the agreement of measured and estimated serum osmolality during the infusion of the two experimental agents. We used Bland and Altman’s limits of agreement analysis to clarify the accuracy of estimated serum osmolality. Bias and upper and lower limits of agreement of bias were calculated.

Results

For each formula, the bias was statistically lower in hypertonic saline group than mannitol group (p < 0.001). Within group comparison showed that the lowest bias (6.0 [limits of agreement: −18.2 to 30.2] and 0.8 [−12.9 to 14.5] mOsml/kg in mannitol group and hypertonic saline group, respectively) was derived from the formula ‘2 × ([serum sodium] + [serum potassium]) + [blood urea nitrogen] + [blood glucose]’.

Conclusions

Compared to mannitol, a better agreement between measured and estimated serum osmolality was found during the infusion of hypertonic saline. This result indicates that, if hypertonic saline is chosen to prevent or treat brain edema, calculated serum osmolality can be used as a reliable surrogate for osmolality measurement.

Trial registration

ClinicalTrials.gov identifier: NCT02037815

Keywords

Serum osmolality Measurement Estimation Correlation Mannitol Hypertonic saline Craniotomy

Background

Brain edema and elevated intracranial pressure (ICP) are potentially devastating complications following various types of intracranial operations [13], and appropriate treatments improve cerebral perfusion and reduce damage by local compression of brain tissue [4, 5]. Hyperosmolar agents have been used to ameliorate brain edema and intracranial hypertension during and after craniotomy, where mannitol and hypertonic saline (HS) are the two most extensively studied and most frequently used in the clinical practice [612]. Although recent meta-analyses suggested that HS might be more effective than mannitol in controlling intracranial hypertension, no significant differences have been found in neurological outcome and side effects between the two agents [1316].

The primary mechanism of hyperosmolar agents to control brain edema is based on the increased osmotic gradient across blood–brain barrier during drug infusion, and this helps in the removal of water from brain tissue to the intravascular space [17]. Clinical studies showed that an osmotic gradient between blood and brain of just above 10 mOsmol/kg was effective in reducing ICP [18]. In clinical practice, serum osmolality can be used as a surrogate measure of the effect of hyperosmolar agents, with either mannitol or HS. The initial target of serum osmolality is often set slightly above the upper limit of normal range [10]. Acute renal failure might develop when serum osmolality exceeds 320 mOsmol/kg during mannitol infusion [19]. Therefore, measurement of serum osmolality during hyperosmolar agent infusion is of clinical importance to determine clinical efficacy, adjust dosage and avoid side effects.

Serum osmolality is often measured in laboratory by cryoscopic technique as the reference method [20]. However, in clinical setting, routine measurement of serum osmolality is not always feasible at bedside, either in intensive care unit (ICU) or in the neurosurgical ward. In this situation, clinicians usually estimate serum osmolality by using formulas derived from serum osmoles that can be measured by bedside blood gas analysis or routine laboratory chemical analysis, such as serum sodium, potassium, urea, and glucose [21]. However, several studies have shown that during mannitol infusion, calculated serum osmolality may lead to a systematic bias compared to direct measurement [2224]. This poor agreement of measured and calculated osmolality during mannitol infusion might be due to the osmolal gap, which is the difference between the two values. Up to now, few studies have been carried out to determine the accuracy of serum osmolality estimation during HS infusion [23]. In the present study, mannitol or HS was used in patients after elective craniotomy, and serum osmolality was measured during drug infusion. Four most cited formulas were chosen to estimate the serum osmolality [21]. Parameters in these formulas are easily collected in clinical practice. The aim was to determine the accuracy of serum osmolality estimation during the application of hyperosmolar agents. We hypothesized that the agreement of measured and calculated serum osmolality during the infusion of HS would be better than mannitol.

Methods

IRB/Consent

The trial complied with the latest Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (IRB) of Beijing Tiantan Hospital, Capital Medical University (KY-2013-002-003). Patients’ conscious state was impaired after surgery; therefore, we obtained written consent from patients’ relatives.

Clinical Trial Registration

The study was registered on January 16, 2014 at the ClinicalTrials.org (NCT02037815). The study protocol was published in April, 2014 [25]. There were two major changes in data analysis. First, the primary outcome was changed from the correlation of measured and estimated serum osmolality to the agreement of these two parameters. Second, the limits of agreement analysis was changed to Bland-Altman method for repeated data.

Study design, setting and participants

We conducted a prospective, randomized, double-blinded, controlled, parallel-group trial in the neurosurgical ICU (30-bed), Beijing Tiantan Hospital (1100-bed), Capital Medical University, Beijing, China, from January to May 2014.

All patients after elective intracranial surgery admitted to our ICU were screened daily for study eligibility.

Inclusion criteria were as follows:
  • Age between 18 and 65 years;

  • Within 24 h after operation;

  • Hyperosmolar agents were required for the prevention or treatment of post-operative brain edema.

Exclusion criteria were:
  • History of diabetes;

  • History of alcohol abuse;

  • Herniation of brain;

  • Unstable hemodynamic condition: systolic blood pressure (BP) less than 90 mmHg or need for continuous infusion of vasopressor;

  • Presence of oliguric renal failure;

  • Serum sodium concentration below 130 mmol/L or above 155 mmol/L;

  • Enrolled in another trial.

Patients were enrolled only once unless they were discharged from the hospital and were readmitted beyond 180 days of the first enrollment.

After randomization (computer generated random digits table in sealed and numbered envelopes), enrolled patients were assigned 1:1 to receive 125 mL of either 20 % mannitol (M group) or 3.1 % sodium chloride solution (HS group). A pharmacist filled 125 mL 20 % mannitol or 3.1 % sodium chloride solution into a sterile 250 mL glass bottle. Patients and all study personnel except the investigative pharmacist were blind to treatment assignment. These concentrations and doses of hyperosmolar agents were chosen according to our standard clinical practice for the prevention and treatment of post-operative brain edema in patients after craniotomy. Indications included intracranial ICP above 25 mmHg, brain edema shown by CT, or poor neurological status considered due to brain edema and bulging of brain during operation. In our institute, the ICP monitoring was performed in patients with external ventricular drainage (Medtronic Neurosurgery, Goleta, CA, USA). Hyperosmolar agents were initiated in some cases because of clinical decline or elevated ICP, but in many others they were instituted based on CT results or empirically.

Data collection and trial intervention

At study entry, data on demography, body mass index, history of illness, diagnoses of the patients, duration of operation, and type and amount of hyperosmolar agents used during 24 h before the study drug infusion were recorded. Acute Physiology and Chronic Health Evaluation II score (APACHE II) was calculated. Venous blood sample (3 mL) was obtained and concentrations of serum glucose, triglyceride, cholesterase, albumin, globulins, total serum protein and blood urea nitrogen (BUN) were measured by standard central laboratory device. The reasons for the use of experimental hyperosmolar agents were also documented.

After enrollment of the patient, 125 ml of either 20 % mannitol (M group) or 3.1 % sodium chloride solution (HS group) was infused via central venous line in 15 min by using an infusion pump. Type of fluid intake, cumulative fluid intake, urine output and fluid balance (intake minus output) were documented immediately before the infusion of study agents (T0), 15 min (T15min), 30 min (T30min), 60 min (T60min), 120 min (T120min), 240 min (T240min) and 360 min (T360min) after the start of experimental agents’ infusion. At the same time points, 3 mL arterial blood sample and 10 mL urine sample were collected. Serum and urine osmolality were measured by means of freezing point depression [20]. Blood values of sodium, potassium, and glucosewere measured using an ICU bedside blood gas analyzer. Urine specific gravity and concentration of sodium were also measured by standard central laboratory devices.

Calculation of serum osmolality and osmolal gap

We used four formulas to estimate serum osmolality [21]

2 × [Na+](Formula 1)

2 × ([Na+] + [K+]) + BG + BUN (Formula 2)

2 × [Na+] + 0.9 × BG + 0.93 × BUN × 0.5 (Formula 3)

1.9 × ([Na+] + [K+]) + BG + BUN × 0.5 + 5 (Formula 4)

[Na+], serum sodium concentration (mmol/L); [K+], serum potassium concentration (mmol/L); BG, blood glucose concentration (mmol/L); BUN, blood urea nitrogen (mmol/L).

Osmolal gap was calculated as the difference between the measured values and each of the estimated values by different formulas shown above.

Outcome measures

The primary outcome was the agreement of measured and estimated serum osmolality (osmolal gap) during the infusion of hyperosmolar agent. The differences between the measured and each of the calculated values from different formulas were compared. Other outcome measures included changes in the following values during the infusion of experimental agents: serum and urine osmolality, serum and urine sodium concentration, urine specific gravity and fluid balance variables.

Statistical analysis

Previous investigation showed that by using the formula 2 listed above, the peak serum osmolal gap during mannitol infusion was 25 mOsmol/kg in patients with brain injury [22]. We hypothesized that the serum peak osmolal gap would decrease to 15 mOsmol/kg during the infusion of 3.1 % sodium chloride solution. Using the Power and Sample Size Calculation program, we needed to enroll 15 patients in each group to be able to reject the null hypothesis that the mean peak serum osmolal gap of the two experimental groups was equal with a probability (power) of 0.8. The Type I error probability with testing this null hypothesis was 0.05.

All analyses were according to the intention-to-treat principle, that was, all randomized patients were analysed in the groups to which they had been originally allocated and were blinded to treatment assignment.

Categorical variables were presented as numbers and percentages and analyzed by the χ2 test. Continuous variables were checked for normal distribution and presented as mean and SD or median and IQR as appropriate. Comparison of continuous variables was performed by using Student t test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables.

We used Bland and Altman’s [26] limits of agreement analysis to clarify the accuracy of estimated serum osmolality calculated by each of the four formulas listed above. Bias was defined as the mean of the difference between measured and calculated values (measured minus calculated). SD of the mean bias was calculated according to the agreement between methods of measurement with multiple observations per individual [27]. Upper and lower limits of agreement were defined as bias ± 1.96 SD of the mean bias.

We used repeated measures of analysis of variance for comparing serum osmolal gap, serum and urine osmolality, serum and urine sodium concentration, urine specific gravity and fluid balance variables across different time points (T0 to T360min) between the two groups (M and HS groups).

All tests of significance were at 0.05. Analyses were conducted using SPSS V.17.0.

Results

Between January and May 2014, 613 patients after elective intracranial surgery were admitted to the ICU and screened for study eligibility. Hyperosmolar agents were required in 187 patients for the prevention or treatment of post-operative brain edema. Among these patients, 35 were enrolled and randomly assigned to M group or HS group. Figure 1 shows the flow chart of patient participation. All patients completed the study intervention and data analysis.
Fig. 1

The flow chart of patient participation

The enrolled patients comprised 18 males (51 %) and 17 females (49 %) with mean (±SD) age of 45 (±12) years. All patients’ diagnoses were brain tumor. Baseline characteristics are shown in Table 1.
Table 1

Baseline characteristics of the patients according to randomization groups

Characteristics

M group (n = 18)

HS group (n = 17)

Age, years

44 ± 14

46 ± 10

Male

9 (50.0 %)

9 (52.9 %)

Body mass index

23.3 ± 4.7

24.5 ± 2.5

Operation time, h

5.1 ± 1.3

4.0 ± 1.0

Use of mannitol before the study

  

 Incidence

4 (22 %)

5 (29 %)

 Time of use before the study, h

10.3 ± 3.3

12.6 ± 3.3

Serum biochemistry

  

 Sodium, mmol/L

137 ± 2

138 ± 3

 Potassium, mmol/L

3.5 ± 0.3

3.5 ± 0.4

 Glucose, mmol/L

6.66 ± 1.80

6.83 ± 1.64

 Triglyceride, mmol/L

1.57 ± 0.27

1.64 ± 0.21

Cholesterase, mmol/L

4.21 ± 0.75

4.32 ± 1.02

Albumin, g/L

37.6 ± 3.4

36.8 ± 4.5

 Globulins, g/L

24.8 ± 3.9

23.7 ± 3.2

 Total protein, g/L

62.4 ± 6.6

60.5 ± 7.1

 Blood urea nitrogen, mmol/L

3.9 ± 1.8

4.0 ± 1.2

APACHE II

15 ± 2

14 ± 3

Reason for use of hyperosmolar agents

  

 Treatment

5 (28 %)

5 (29 %)

 Prevention

13 (72 %)

12 (71 %)

Data are presented as mean ± SD or number (%). APACHE II: Acute Physiology and Chronic Health Evaluation II score

Serum osmolality were measured 7 times in each patient, from immediately before (T0) to 360 min (T360min) after the start of experimental agentsinfusion. At the same time points, blood concentrations of sodium, potassium, and glucose were also measured. Blood concentration of BUN was only measured at T0. Four formulas were used to calculate serum osmolality. So, 245 paired data sets (126 in M group and 119 in HS group) were obtained, which comprised measured and four estimated serum osmolality. Table 2 shows the results of Bland and Altman’s limits of agreement analysis. For each formula, bias was statistically lower in HS group than in M group (p < 0.001). Within group comparison showed that, either in M group or in HS group, there was significant difference in bias across any of the four formulas (p < 0.001). The lowest bias with narrowest limits of agreement between the measured and estimated serum osmolality was derived from the formula 2, with 6.0 (−18.2 to 30.2) and 0.8 (−12.9 to 14.5) mOsmol/kg in M group and HS group, respectively (Table 2).
Table 2

Bland and Altman’s limits of agreement analysis between measured and calculated serum osmolality (mOsmol/kg) by the four formulas

Formulas

M group (126 pairs)

HS group (119 pairs)

Bias

Limits of agreement

Bias

Limits of agreement

1

25.0

2.6 to 47.5

19.5

5.1 to 33.8

2

6.0

−18.2 to 30.2

0.8

−12.9 to 14.5

3

16.3

−7.5 to 40.2

11.3

−2.1 to 24.8

4

17.3

−6.2 to 40.7

12.6

−0.6 to 25.7

Data are presented as bias and lower to upper limits of agreement. The differences between measured and calculated serum osmolality were calculated in each data set. Bias was defined as the mean of difference between the measured and calculated values. SD of the mean bias was calculated according to the agreement between methods of measurement with multiple observations per individual. Upper and lower limits of agreement were defined as bias ± 1.96 SD

Patients in M group or HS group received 125 ml of either 20 % mannitol or 3.1 % sodium chloride solution, respectively

For each formula, the bias in HS group was statistically lower than in M group (p < 0.001). Within group comparison showed that, either in M group or in HS group, there was significant difference in bias between any of the two formulas (p < 0.001)

Table 3 shows variables of osmolality, electrolytes, and fluid balance during the infusion of experimental agents. After the infusion of hyperosmolar agents, serum osmolality increased statistically to the peak value (301.6 ± 10.5 [p < 0.001] and 299.6 ± 7.3 [p < 0.001] mOsmol/kg in M group and HS group, respectively) at T15min in both groups, and no significant differences were found between the two groups at any time point (p = 0.515). In M group, serum osmolality at T15min and T30min were statistically higher than values at baseline and other time points (p < 0.05), whereas values at T240min and T360min decreased statistically below the baseline value (p < 0.05). The change of serum osmolality in HS group exhibited the same tendency as in M group. However, in HS group, serum osmolality at T240min (p = 0.810) and T360min (p = 0.076) were not statistically different from baseline value.
Table 3

Variables of osmolality, electrolytes, and fluid balance during the infusion of experimental agents

Variables

Time

M group

HS group

p value

Serum osmolality, mOsmol/kg

T0

296.3 ± 11.2bcfg

295.7 ± 7.4bcd

0.847

T15min

301.6 ± 10.5acdefg

299.6 ± 7.3acdefg

0.515

T30min

298.9 ± 10.1abdefg

298.4 ± 7.4abefg

0.875

T60min

297.0 ± 8.3bcfg

297.8 ± 7.0abfg

0.770

T120min

296.7 ± 9.7bcfg

296.6 ± 6.6bcg

0.963

T240min

294.9 ± 10.3abcdeg

295.9 ± 6.5bcdg

0.751

T360min

292.4 ± 9.1abcdef

294.1 ± 6.6bcdef

0.527

Serum osmolal gap*, mOsmol/kg

T0

3.6 ± 12.1bcgf

2.2 ± 6.9b

0.684

T15min

16.4 ± 11.4acdefg

−0.9 ± 6.2acd

<0.001

T30min

10.8 ± 12.3abdefg

2.0 ± 6.9b

0.014

T60min

5.3 ± 8.9bcfg

1.3 ± 6.8b

0.142

T120min

3.7 ± 11.1bcg

0.8 ± 7.2

0.368

T240min

2.4 ± 12.1bcd

−0.1 ± 8.1

0.470

T360min

−0.1 ± 10.1abcde

0.2 ± 6.5

0.905

Serum sodium, mmol/L

T0

137.0 ± 2.1bc

137.3 ± 2.8bcd

0.723

T15min

133.6 ± 2.6acdefg

141.4 ± 3.1acdefg

<0.001

T30min

134.9 ± 3.1abdef

139.2 ± 3.5abg

0.001

T60min

136.6 ± 2.8bc

139.1 ± 3.2abg

0.018

T120min

136.8 ± 3.4bc

138.5 ± 3.7b

0.164

T240min

136.4 ± 3.2bc

138.1 ± 3.3b

0.139

T360min

136.1 ± 3.5b

137.5 ± 2.9bcd

0.202

Urine osmolality, mOsmol/kg

T0

825.8 ± 92.1bcde

824.2 ± 181.3bcdef

0.973

T15min

659.0 ± 123.0aefg

727.4 ± 181.1a

0.198

T30min

638.1 ± 80.1adefg

692.6 ± 186.2adfg

0.264

T60min

677.7 ± 79.0acefg

731.1 ± 169.2ac

0.236

T120min

727.3 ± 84.9abcdfg

719.3 ± 182.2a

0.868

T240min

788.5 ± 92.0bcde

738.7 ± 209.3ac

0.354

T360min

808.9 ± 162.9bcde

759.8 ± 224.3c

0.461

Urine sodium, mmol/L

T0

199.2 ± 44.2bcdefg

218.8 ± 63.3f

0.294

T15min

115.4 ± 30.6af

210.5 ± 59.8f

<0.001

T30min

106.7 ± 22.1adfg

214.7 ± 44.4ef

<0.001

T60min

116.6 ± 30.7acf

214.6 ± 47.8ef

<0.001

T120min

116.8 ± 36.5af

199.1 ± 50.1cd

<0.001

T240min

140.9 ± 33.5abcde

184.7 ± 51.7abcd

0.005

T360min

137.4 ± 53.0ac

195.1 ± 56.3d

0.004

Urine SG, kg/m3

T0

1.030 ± 0.007

1.028 ± 0.007bcdefg

0.421

T15min

1.029 ± 0.006e

1.023 ± 0.007a

0.007

T30min

1.029 ± 0.006e

1.021 ± 0.007adef

<0.001

T60min

1.031 ± 0.006

1.022 ± 0.006ac

<0.001

T120min

1.033 ± 0.006bc

1.022 ± 0.006ac

<0.001

T240min

1.032 ± 0.006

1.023 ± 0.007ac

<0.001

T360min

1.030 ± 0.009

1.023 ± 0.007a

0.008

Cumulative fluid intake, mL

T0

0

0

/

T15min

132 ± 16

131 ± 18

0.973

T30min

179 ± 23

187 ± 30

0.419

T60min

280 ± 84

257 ± 51

0.344

T120min

423 ± 102

381 ± 93

0.218

T240min

617 ± 144

647 ± 139

0.536

T360min

813 ± 186

855 ± 219

0.537

Cumulative urine output, mL

T0

0

0

/

T15min

76 ± 45

49 ± 22

0.035

T30min

167 ± 66

94 ± 37

<0.001

T60min

300 ± 108

171 ± 71

<0.001

T120min

449 ± 155

303 ± 121

0.004

T240min

662 ± 183

537 ± 189

0.050

T360min

835 ± 221

775 ± 253

0.455

Cumulative fluid balance, mL

T0

0

0

/

T15min

56 ± 47

83 ± 28

0.051

T30min

12 ± 69

93 ± 49

<0.001

T60min

−20 ± 139

86 ± 84

0.010

T120min

−26 ± 179

79 ± 131

0.058

T240min

−45 ± 233

110 ± 194

0.042

T360min

−23 ± 267

81 ± 255

0.250

Data are presented as mean ± SD

Urine SG urine specific gravity

*: Calculated osmolality was derived from formula 2

: Fluid balance = intake-output

P Values represent between group comparisons. Within group comparisons are labeled as: astatistically different compared to T0; b to T15min; c to T30min; d to T60min; e to T120min; f to T240min; g to T360min

Since serum osmolality was higher at T15min and T30min in both M group and HS group, we combined the data at this two time points to determine whether desired serum osmolality was achieved. In M group, 4 (11.1 %) measurements were greater than 310 mOsmol/kg, 3 (8.3 %) measurements were lower than 290 mOsmol/kg, while 27 (80.6 %) measurements were between 290 and 310 mOsmol/kg. In HS group, 4 (11.8 %) measurements were greater than 310 mOsmol/kg while other measurements were between 290 and 310 mOsmol/kg (Fig. 2).
Fig. 2

Distribution of serum osmolality at T15min to T30min

Because the lowest bias between measured and estimated serum osmolality was derived from the formula 2 (Table 2), serum osmolal gap was calculated according to this formula. In M group, after the infusion of mannitol, osmolal gap increased statistically at T15min (16.4 ± 11.4 mOsmol/kg, p < 0.001) and T30min (10.8 ± 12.3 mOsmol/kg, p < 0.001), and decreased to the baseline level at time points of T60min to T240min, then further decreased statistically below the baseline value at T360min (p = 0.002, Table 3). In HS group, the osmolal gap at T15min (−0.9 ± 6.2 mOsmol/kg, p = 0.029) was slightly but significantly lower than the baseline value (Table 3). No significant differences were found among values at baseline and at the time points from T30min to T360min (p > 0.05). Between groups comparison showed statistically higher osmolal gap at T15min (p < 0.001) and T30min (p = 0.014) in M group than HS group, but no significant differences existed at time points from T60min to T360min (p > 0.05).

After the infusion of experimental agents, tendency of change in serum sodium differed statistically between the two groups (Table 3). In M group, after mannitol infusion, serum sodium decreased statistically from 137.0 ± 2.1 mmol/L at baseline to 133.6 ± 2.6 mmol/L at T15min (p < 0.001) and 134.9 ± 3.1 mmol/L at T30min (p = 0.001). In HS group, serum sodium increased statistically from 137.3 ± 2.8 mmol/L at baseline to 141.4 ± 3.1 mmol/L at T15min (p < 0.001), and maintained statistically greater than baseline at T30min (p = 0.002) and T60min (p = 0.015).

The tendency of change in urine osmolality did not differ between the two groups (Table 3). After the infusion of study agents, urine osmolality decreased statistically at time points from T15min to T120min (p < 0.05), and then recovered to baseline level. For urine sodium, significant differences were found between the two groups at all time points after the infusion of study agents (p < 0.05). After the infusion of mannitol, urine sodium decreased statistically (p < 0.001). However, in HS group, urine sodium did not change statistically (p > 0.05, only slightly decreased at T240min [p = 0.007]). Significant difference was also found in urine specific gravity after study agents’ infusion between the two groups (p < 0.05). Urine specific gravity in M group did not change statistically during the study (p > 0.05), but in HS group, this parameter decreased statistically after infusion and remained in the level below baseline (p < 0.05).

We also collected data of fluid balance during the study period (Table 3). For cumulative fluid intake, there was no significant difference between the two groups (p > 0.05). However, cumulative urine output in M group was statistically higher than HS group, from T15min to T240min (662 ± 183 mL in M group and 537 ± 189 mL in HS group, p < 0.05). This resulted in the significant differences in cumulative fluid balance between the two groups. Cumulative fluid balance was statistically more negative in M group than HS group at T30min, T60min and T240min (p < 0.05).

Discussion

In this prospective, double-blinded, randomized controlled trial, we determined the agreement of measured and estimated serum osmolality during theoretically equiosmolar load of mannitol and HS, and compared the accuracy of serum osmolality estimation derived from four common used formulas between the two agents. The main findings of our study are that, (1) calculation by using the formula ‘2 × ([Na+] + [K+]) + BUN + BG’ provides the most accurate estimation of serum osmolality after the infusion of HS; (2) an increase of serum osmolality is observed after the infusion of either 20 % mannitol or 3.1 % HS, and with the latter this is associated with the increase in serum sodium concentration; and (3) compared with HS, mannitol results in an abrupt and significant increase in osmolal gap during the early stage after the infusion.

Hyperosmolar agents are frequently used in prevention and treatment of brain edema during and after craniotomy and monitoring of serum osmolality is essential in this situation [612]. A lot of formulas have been published for the application of serum osmolality estimation in general patients population [21]. Among these formulas, several have been evaluated in neurological and neurosurgical patients during the administration of hyperosmolar agents [2224]. In these studies, different formulas were used and different patients were enrolled (not treated with hyperosmolar agents [24], treated with mannitol [22] or treated with both mannitol and HS [23]). The results showed a suboptimal correlation between measured and calculated serum osmolality during mannitol administration [22, 23]. Although patients receiving mannitol and HS were both enrolled in the study of Vialet et al., results of mannitol and HS were not reported separately [23]. In present study, we chose 4 most cited formulas [21], and confirmed the most accurate formula for the estimation of serum osmolality. Our results indicate that, if HS is chosen to prevent or treat brain edema during post-operative period, calculated serum osmolality can be used as a reliable surrogate for osmolality measurement.

In the present study, the theoretically equiosmolar bolus of either mannitol or HS resulted in an abrupt increase in serum osmolality, reaching the peak value by the end of infusion (Table 3). This is consistent with the results of previous studies [6, 7]. In Rozet et al. study, 5 ml/kg of 20 % mannitol and 3 % HS were administered over 15 min, and both resulted in similar increase in serum osmolality [6]. Francony et al. compared a single infusion of either 231 mL of 20 % mannitol or 100 mL of 7.45 % HS during 20 min of administration [7]. The baseline serum osmolality was not significant different between the two groups, with 296 ± 11 and 292 ± 13 mOsmol/kg in mannitol group and HS group, respectively. Both agents caused 2 % increases in serum osmolality at 30 min after the infusion, also with no difference between the two groups. However, in our study, we found that the magnitude of increase in serum osmolality was higher, although not significantly, after the infusion of 20 % mannitol than 3.1 % HS (Table 3). Calculated osmolality of 20 % mannitol (1098 mosmol/kg) and 3.1 % sodium chloride solution (1054 mosmol/kg) are nearly equal, but measured values are not. By means of freezing point depression, we found that the real osmolality of 20 % mannitol and 3.1 % HS were about 1378 and 972 mOsmol/kg, respectively. According to this result, 4.3 % HS (about 1341 mOsmol/kg) should be used to as the equal-osmolar hyperosmolar agent with 20 % mannitol.

Up to now, only one study investigated osmolal gap during HS infusion. Vialet et al. enrolled 20 patients with traumatic brain injury, who received 2 mL/kg of either 20 % mannitol (n = 10) or 7.5 % HS (n = 10) in 20 min [23]. By using the formula ‘2 × [Na+] + BUN + BG’, they found an osmolal gap of −2.3 ± 7.2 mOsmol/kg in this population, but unfortunately the respective value in mannitol and HS group was not reported separately. In our study, we calculated the osmolal gap by using the formula ‘2 × ([Na+] + [K+]) + BUN + BG’, and found a different pattern of change in osmolal gap after the infusion of mannitol and HS (Table 3). Osmolal gap increased statistically at 15 to 30 min after the infusion of mannitol, whereas remained almost unchanged after the infusion of HS (slightly decreased at 15 min). The increasing of serum osmolal gap after mannitol infusion was mainly due to the inverse change of serum sodium concentration after the infusion of the two agents. The dynamic changes of serum sodium during the administration of mannitol and HS in present study were comparable to previous reports [69, 28, 29]. The infusion of mannitol attracts water from interstitial space to intravascular space, which results in transient intravascular volume expansion and dilutional hyponatremia.

In the present study, we also determined the influence of hyperosmolar agents on fluid and urine variables (Table 3). Since the cumulative fluid intake was not different between the two groups, higher cumulative urine output after mannitol infusion resulted in a more negative fluid balance. This is in accordance with the effect of osmotic diuresis with mannitol infusion reported in previous studies [68, 30, 31]. These results suggest that different strategy should be employed during mannitol and HS therapy. Hypovolemia should be avoided after mannitol infusion, whereas hypervolemia be avoided after HS infusion.

There are some limitations to this study. First, although it was not surprising that we found a lower osmolal gap after the infusion of HS than mannitol, the most reliable formulas for serum osmolality estimation was identified in present study. Second, the doses of mannitol and HS prepared and used in present study were not actually equiosmolar. This is the same problem in other studies for the comparison of equiosmolar hyperosmolar solutions [68]. We found that 20 % mannitol (1378 mOsmol/kg) and 4.3 % HS (1341 mOsmol/kg) were measured equiosmolar. Third, we only determined the change of osmolality after single bolus of hyperosmolar agents. In clinical practice, hyperosmolar agents are usually given several times to maintain a hyperosmolar state. Our results cannot be applied to repeated use of hyperosmolar agents. Fourth, we did not investigate the effect of hyperosmolar agents on intracranial pressure and other clinical outcomes. However, this is beyond the scope of our study.

To our knowledge, this is the first prospective, randomizedcontrolled, double-blinded human study comparing the agreement of measured and estimated serum osmolality during the infusion of mannitol and HS. The results indicate that, if HS is chosen to prevent or treat brain edema during post-operative period, calculated serum osmolality can be used as a reliable surrogate for osmolality measurement.

Conclusions

Compared to mannitol, a better agreement between measured and estimated serum osmolality was found during the infusion of hypertonic saline. This result indicates that, if hypertonic saline is chosen to prevent or treat brain edema, calculated serum osmolality can be used as a reliable surrogate for osmolality measurement.

Notes

Abbreviations

ICP: 

Intracranial pressure

HS: 

Hypertonic saline

ICU: 

Intensive care unit

BP: 

Blood prssure

M: 

Mannitol

APACHE II: 

Acute physiology and chronic health evaluation II

BUN: 

Blood urea nitrogen

BG: 

Blood glucose concentration

Declarations

Acknowledgments

We would like to thank Ms. Na Rong for her excellent advices on English writing. The study was supported by Beijing Tiantan Hospital, Capital Medical University (No.ZX2011 -02), and the Beijing Municipal Administration of Hospital (No: ZYLX201502). The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University

References

  1. Bruder N, Ravussin P. Recovery from anesthesia and postoperative extubation of neurosurgical patients: a review. J Neurosurg Anesthesiol. 1999;11(4):282–93.View ArticlePubMedGoogle Scholar
  2. Wong JM, Panchmatia JR, Ziewacz JE, Bader AM, Dunn IF, Laws ER, et al. Patterns in neurosurgical adverse events: intracranial neoplasm surgery. Neurosurg Focus. 2012;33(5), E16. doi:https://doi.org/10.3171/2012.7.FOCUS12183.View ArticlePubMedGoogle Scholar
  3. McLaughlin N, Bojanowski MW. Early surgery-related complications after aneurysm clip placement: an analysis of causes and patient outcomes. J Neurosurg. 2004;101(4):600–6. doi:https://doi.org/10.3171/jns.2004.101.4.0600.View ArticlePubMedGoogle Scholar
  4. Bingaman WE, Frank JI. Malignant cerebral edema and intracranial hypertension. Neurol Clin. 1995;13(3):479–509.PubMedGoogle Scholar
  5. Rabinstein AA. Treatment of cerebral edema. Neurologist. 2006;12(2):59–73. doi:https://doi.org/10.1097/01.nrl.0000186810.62736.f0.View ArticlePubMedGoogle Scholar
  6. Rozet I, Tontisirin N, Muangman S, Vavilala MS, Souter MJ, Lee LA, et al. Effect of equiosmolar solutions of mannitol versus hypertonic saline on intraoperative brain relaxation and electrolyte balance. Anesthesiology. 2007;107(5):697–704. doi:https://doi.org/10.1097/01.anes.0000286980.92759.94.View ArticlePubMedGoogle Scholar
  7. Francony G, Fauvage B, Falcon D, Canet C, Dilou H, Lavagne P, et al. Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure. Crit Care Med. 2008;36(3):795–800. doi:https://doi.org/10.1097/ccm.0b013e3181643b41.View ArticlePubMedGoogle Scholar
  8. Wu CT, Chen LC, Kuo CP, Ju DT, Borel CO, Cherng CH, et al. A comparison of 3 % hypertonic saline and mannitol for brain relaxation during elective supratentorial brain tumor surgery. Anesth Analg. 2010;110(3):903–7. doi:https://doi.org/10.1213/ANE.0b013e3181cb3f8b.View ArticlePubMedGoogle Scholar
  9. Cottenceau V, Masson F, Mahamid E, Petit L, Shik V, Sztark F, et al. Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011;28(10):2003–12. doi:https://doi.org/10.1089/neu.2011.1929.View ArticlePubMedGoogle Scholar
  10. Diringer MN, Zazulia AR. Osmotic therapy: fact and fiction. Neurocrit Care. 2004;1(2):219–33.View ArticlePubMedGoogle Scholar
  11. Ropper AH. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med. 2012;367(8):746–52. doi:https://doi.org/10.1056/NEJMct1206321.View ArticlePubMedGoogle Scholar
  12. Hays AN, Lazaridis C, Neyens R, Nicholas J, Gay S, Chalela JA. Osmotherapy: use among neurointensivists. Neurocrit Care. 2011;14(2):222–8. doi:https://doi.org/10.1007/s12028-010-9477-4.View ArticlePubMedGoogle Scholar
  13. Kamel H, Navi BB, Nakagawa K, Hemphill 3rd JC, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39(3):554–9. doi:https://doi.org/10.1097/CCM.0b013e318206b9be.View ArticlePubMedGoogle Scholar
  14. Mortazavi MM, Romeo AK, Deep A, Griessenauer CJ, Shoja MM, Tubbs RS, et al. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg. 2012;116(1):210–21. doi:https://doi.org/10.3171/2011.7.JNS102142.View ArticlePubMedGoogle Scholar
  15. Lazaridis C, Neyens R, Bodle J, DeSantis SM. High-osmolarity saline in neurocritical care: systematic review and meta-analysis. Crit Care Med. 2013;41(5):1353–60. doi:https://doi.org/10.1097/CCM.0b013e31827ca4b3.View ArticlePubMedGoogle Scholar
  16. Rickard AC, Smith JE, Newell P, Bailey A, Kehoe A, Mann C. Salt or sugar for your injured brain? A meta-analysis of randomised controlled trials of mannitol versus hypertonic sodium solutions to manage raised intracranial pressure in traumatic brain injury. Emerg Med J. 2013;31(8):679–83. doi:https://doi.org/10.1136/emermed-2013-202679.View ArticlePubMedGoogle Scholar
  17. Fink ME. Osmotherapy for intracranial hypertension: mannitol versus hypertonic saline. Continuum. 2012;18(3):640–54. doi:https://doi.org/10.1212/01.CON.0000415432.84147.1e.PubMedGoogle Scholar
  18. Rottenberg DA, Hurwitz BJ, Posner JB. The effect of oral glycerol on intraventricular pressure in man. Neurology. 1977;27(7):600–8.View ArticlePubMedGoogle Scholar
  19. Visweswaran P, Massin EK, Dubose Jr TD. Mannitol-induced acute renal failure. J Am Soc Nephrol. 1997;8(6):1028–33.PubMedGoogle Scholar
  20. Sweeney TE, Beuchat CA. Limitations of methods of osmometry: measuring the osmolality of biological fluids. Am J Physiol. 1993;264(3 Pt 2):R469–80.PubMedGoogle Scholar
  21. Fazekas AS, Funk GC, Klobassa DS, Ruther H, Ziegler I, Zander R, et al. Evaluation of 36 formulas for calculating plasma osmolality. Intensive Care Med. 2013;39(2):302–8. doi:https://doi.org/10.1007/s00134-012-2691-0.View ArticlePubMedGoogle Scholar
  22. Garcia-Morales EJ, Cariappa R, Parvin CA, Scott MG, Diringer MN. Osmole gap in neurologic-neurosurgical intensive care unit: its normal value, calculation, and relationship with mannitol serum concentrations. Crit Care Med. 2004;32(4):986–91.View ArticlePubMedGoogle Scholar
  23. Vialet R, Leone M, Albanese J, Martin C. Calculated serum osmolality can lead to a systematic bias compared to direct measurement. J Neurosurg Anesthesiol. 2005;17(2):106–9.View ArticlePubMedGoogle Scholar
  24. Acikgoz S, Can M, Mungan AG, Ataymen M, Sumbuloglu V, Gul S. Comparison of the calculated and measured osmolality in intracranial bleeding and head injury patients. J Emerg Med. 2009;36(2):217–9. doi:https://doi.org/10.1016/j.jemermed.2007.11.075.View ArticlePubMedGoogle Scholar
  25. Li Q, Xu M, Zhou JX. Correlation of measured and calculated serum osmolality during mannitol or hypertonic saline infusion in patients after craniotomy: a study protocol and statistical analysis plan for a randomised controlled trial. BMJ Open. 2014;4(4), e004921. doi:https://doi.org/10.1136/bmjopen-2014-004921.View ArticlePubMedPubMed CentralGoogle Scholar
  26. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1(8476):307–10.View ArticlePubMedGoogle Scholar
  27. Bland JM, Altman DG. Agreement between methods of measurement with multiple observations per individual. J Biopharm Stat. 2007;17(4):571–82. doi:https://doi.org/10.1080/10543400701329422.View ArticlePubMedGoogle Scholar
  28. Quentin C, Charbonneau S, Moumdjian R, Lallo A, Bouthilier A, Fournier-Gosselin MP, et al. A comparison of two doses of mannitol on brain relaxation during supratentorial brain tumor craniotomy: a randomized trial. Anesth Analg. 2013;116(4):862–8. doi:https://doi.org/10.1213/ANE.0b013e318282dc70.View ArticlePubMedGoogle Scholar
  29. Sakowitz OW, Stover JF, Sarrafzadeh AS, Unterberg AW, Kiening KL. Effects of mannitol bolus administration on intracranial pressure, cerebral extracellular metabolites, and tissue oxygenation in severely head-injured patients. J Trauma. 2007;62(2):292–8. doi:https://doi.org/10.1097/01.ta.0000203560.03937.2d.View ArticlePubMedGoogle Scholar
  30. Tormey WP. Are the increasing clinical demands for osmolality measurements and their associated electrolytes appropriate? Ir J Med Sci. 1997;166(2):75–9.View ArticlePubMedGoogle Scholar
  31. Manninen PH, Lam AM, Gelb AW, Brown SC. The effect of high-dose mannitol on serum and urine electrolytes and osmolality in neurosurgical patients. Can J Anaesth. 1987;34(5):442–6. doi:https://doi.org/10.1007/BF03014345.View ArticlePubMedGoogle Scholar

Copyright

© Li et al. 2015

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