A Comparison of Hypertonic Saline and Mannitol on Intraoperative Brain Relaxation in Patients with Raised Intracranial Pressure during Supratentorial Tumors Resection: A Randomized Control Trial
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.279671
Source of Support: None, Conflict of Interest: None
Keywords: Brain, elevated intracranial pressure, hypertonic saline, mannitol, relaxationKey Messages: Both mannitol and hypertonic saline are equally efficacious in providing intraoperative relaxed brain in patients with the features of raised intracranial pressure. Mean arterial pressure and central venous pressure is better maintained with hypertonic saline.
Hypertonic saline (HTS) or mannitol are being routinely used to treat intracranial hypertension.,,,, Mannitol acts through its osmotic diuretic properties that produce a reduction in brain water content and cerebrospinal fluid (CSF) pressure in approximately 20 min. Besides this, it also reduces intracranial pressure (ICP) through the changes in blood fluid dynamics or blood rheology. Recently, HTS has appeared an appealing alternative to mannitol because its reflection coefficient is higher than that of mannitol (1.0 vs 0.9, respectively). Thus, HTS does not cross the intact blood–brain barrier. Due to this property, HTS causes a greater increase in serum osmolality as compared to mannitol in equiomolar dosage. HTS creates a greater transendothelial osmotic gradient that results in more water movement from interstitial and intracellular brain to the intravascular space. HTS little diuretic effect and thus maintains hemodynamic stability and cerebral perfusion pressures.
Previously published clinical trials comparing the effects of HTS and mannitol have included the patients with varied intracranial pathologies. The protocols of administration of HTS or mannitol and the osmolar load of the compounds were also variable.,,,,, Wu et al. compared these two agents in elective supratentorial tumors for brain relaxation. They excluded the patents with signs of raised ICP. The authors found that brain relaxation was better in the HTS group than the mannitol group during elective supratentorial brain tumor surgery. Rozet et al. also compared 20% mannitol and 3% HS for brain relaxation in patients scheduled to undergo craniotomy for varied neurosurgical pathologies and found that there was no difference in brain relaxation between two groups.
The present study was designed with the primary aim of comparing the effect of near equiosmolar equivolemic solutions of 3% HTS (1,024 mOsm/L) and 20% mannitol (1,098 mOsm/L) on intraoperative brain relaxation in patients with clinical or radiological evidence of raised ICP undergoing surgery for supratentorial tumors. The secondary aim was to compare the electrolyte changes after administering 3% HTS or 20% mannitol in these patients.
This prospective randomized double blind study was approved by the hospital ethics committee (no. MS/1243/MS/8/106). After obtaining written informed patient consent, 30 patients with American Society of Anesthesiologists physical statuses I–III and aged 18–65 years with clinical or radiological evidence of raised ICP, scheduled to undergo supratentorial tumor resection were included in the study [Figure 1]. Clinical signs and symptoms of raised ICP were defined as the presence of bradycardia with hypertension, recurrent vomiting, blurring of vision, behavioral abnormalities, and excessive sleepiness or irritable behavior. Radiological signs were defined as significant midline shift (>5 mm), loss of sulci, loss of gyri, gray and white matter distinction, and significant edema surrounding the tumor. Patients with preoperative hyponatremia or hypernatremia (serum Na <135 or >145 mEq/L), intake of any hyperosmotic fluid (mannitol or HTS) in the previous 24 h, history of congestive heart failure or kidney disease and prior surgery for ventriculo-peritoneal (VP) shunt were excluded.
Patients were randomized using sealed envelopes into two groups; group M, who received 20% mannitol (osmolarity = 1,098 mOsm/l) and group HTS, who received 3% HTS (osmolarity = 1,024 mOsm/l). Patients received 5 ml/kg of either drug for intraoperative brain relaxation. Drugs were loaded in the 50 cc syringes and labeled as the test drug. Both fluids were administered over 15 min using an infusion pump after skin incision via the central line. The anesthesiologist who recorded intraoperated data and the surgeon who assessed the brain relaxation were blinded to the drug being given.
Standard monitors were attached; noninvasive blood pressure (NiBP), electrocardiography (ECG), pulse oximetry (SpO2), end tidal carbon dioxide concentration (EtCO2), and entropy. Anesthesia was induced with propofol and fentanyl, and vecuronium was used to facilitate intubation. Invasive arterial and central venous pressures (CVPs) were also monitored. Anesthesia was maintained using propofol and fentanyl infusion titrated to keep state entropy (SE) between 40 and 60. All patients were ventilated with oxygen-nitrous oxide mixture (50%:50%) to maintain arterial partial pressure of carbon dioxide (PaCO2) between 30 and 35 mm Hg.
Brain relaxation was scored by the surgeon and the anesthetist blinded to the test drug. A four-point scale was used by the surgeon: 1 = perfectly relaxed, 2 = satisfactorily relaxed, 3 = firm brain, 4 = bulging brain. A second bolus of 5 ml/kg of the study drug was given if brain was not relaxed. A three-point scale was used by the anesthetist: = brain fully relaxed, fallen below both outer and inner tables of cranium, moving with respiration and pulsating with heartbeat, 2 = brain partially relaxed, lying between outer and inner tables of cranium, slight movement with respiration and slight pulsation with heartbeat, 3 = brain bulging out of the cranial cavity, no movement with respiration and no pulsation with heartbeat. We have used two scales to rule out the bias by the surgeon. The second scale was designed to include the brain characteristics and parameters, which are less amenable to the bias. The patients who had tight brain interfering the dura opening were managed with transient hyperventilation (EtCO2 up to 25 mm Hg) with optimum airway pressures, mild hypertension, additional dosages of hyperosmolar agent (100 ml mannitol/HTS).
Hemodynamic data and EtCO2 were recorded for comparisons initially at 5 min ( first 15 min after induction) and then at 15 min intervals till end of surgery. Arterial blood gases and electrolytes were measured before and 1 h after giving hypertonic agents. Serum sodium and potassium were measured at 24 and 48 h also. Hourly urine output was recorded.
Considering a significant difference of 1 point in brain relaxation score between the groups to be clinically significant, a power analysis based on 95% confidence interval and with power of 90% revealed a sample size of 30 subjects (15 subjects in each group).
The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 15.0 for Windows). The normality of the data was assessed by measures of skewness and Kolmogorov Smirnov tests of normality. The normally distributed data means were compared using t-test. For skewed data, the Mann-Whitney test was used. The Chi-square or Fisher's exact test was used to compare proportions, whichever was applicable. For time related variables, the Wilcoxon signed or paired t-test was applied. P <0.05 was considered significant. Multivariate analysis of variance (ANOVA) was applied for the comparison of hemodynamic and laboratory variables between the groups.
Demographic and clinical characteristics were comparable between the two groups [Table 1]. There was no statistically significant difference in heart rates between the two groups at various time intervals. There was a significant decrease in mean arterial pressure (MAP) from the preinduction value in group M after 75 min (P< 0.05) whereas in the HTS-group it remained stable. [Figure 2] compares the MAP between the two groups.
Baseline CVP was comparable in both the study groups. There was a consistent rise in CVP in both the group till 1 h. But after 1 h, CVP in the HTS group remained almost the same whereas the CVP in the M group started decreasing. The difference in CVP between the two groups was statistically significant after 45 min of study [Figure 3]. When compared with baseline within the group, after 150 min CVP decreased significantly from baseline in the M group whereas it remained comparable to the baseline in the HTS group. These falls in MAP and CVP in mannitol were not clinically significant and none of the patients required additional treatments for these changes other than intravenous fluid infusion.
The urine output was significantly higher in the M group as compared to the HTS group throughout the study period [Table 2]. Serum sodium was significantly higher in the HTS group but remained within normal limits [Table 2]. Difference in serum K levels was statistically significant at 60 min and 24 h, but returned to baseline at 48 h [Table 2].
There was no significant difference in brain relaxation as assessed by the operating surgeon and anesthesiologist between the two groups [Table 3].
In our study, 20% mannitol and 3% HTS produced a similar effect on brain relaxation. There are various studies in the literature reporting varied results. Two previously published crossover, randomized trials demonstrated higher efficacy of HTS in decreasing ICPs than equimolar infusion of mannitol., The reported longer duration of ICP reduction after the use of HTS could be due to the combination of HTS with 6% hydroxyethyl starch solution or with 6% dextran solution, which are known to prolong the effects of HTS. Previous prospective mannitol and HTS during elective neurosurgery used different osmolar loads of the two agents and reported comparable brain relaxation between groups.,
Rozet et al. compared equiosmolar, equivolemic (5 ml/kg) loads of 20% mannitol and 3% HTS in different surgical setups; supratentorial and infratentorial tumors, arteriovenous malformations, aneurysms, and subarachnoid hemorrhage. They found no difference in brain relaxation in those administered either mannitol or HTS. Here in this study, authors included a varied population and did not standardized the depth of anesthesia. Our study was conducted with similar dosages in patients with the features of raised ICP and found the similar results.
Recently, Ali et al. had conducted a prospective, randomized, double-blind study in patients undergoing elective supratentorial surgeries. They compared received 5 ml/kg 20% mannitol or 3% HS as an infusion for 15 min. The authors monitored ICP using parenchymal monitor and also standardized the anesthesia by monitoring entropy. The authors concluded that 3% HS was more effective in ICP reduction than 20% mannitol during supratentorial tumor surgeries. However, the authors excluded the patients with raised ICP in their study.
In another study, Wu et al. reported better brain relaxation with HTS during elective supratentorial brain tumor surgeries. The authors had used fixed volumes in their study; 160 ml of 3% HTS or 150 ml of 20% mannitol. In addition, the depth of anesthesia was not monitored in these studies, which can affect brain relaxation. We have used a weight-based dosage of 5 ml/kg and entropy to keep the similar depth of anesthesia. This may account for the difference in results.
Dostal et al. compared the infusion of 3.75 ml of equiosmolar concentrations of 3.2% HTS and 20% mannitol (osmolarity 1,099 each) and concluded that the HTS group has better brain relaxation than the mannitol group.
There was a small drop in MAP after induction in both groups. This may be due to the effect of various anesthetic agents. After 30 min, the MAP in the HTS group was maintained near baseline whereas MAP in the mannitol group was lower than baseline throughout the study period. HTS maintains MAP because of increases in cardiac output and intravascular volume. HTS increases cardiac output due to its direct ionotropic effect, derived from improvement in cardiac microcirculation and contractility. Volume expansion occurs because of hyperosmolarity that creates a gradient to move free water from the intracellular and interstitial compartments into the intravascular compartment. High urine output seen with mannitol might lead to the lower CVP. Compared with HTS, mannitol has a more prominent diuretic effect in all the 3 h of observation (P value <0.05). Hypernatremia after HTS was consistent with previous studies.,
Both mannitol and HTS are equally efficacious in reducing the intracranial hypertension. MAP and CVP are better maintained close to the baseline with HTS. Thus, we advocate the use of HTS over mannitol for reducing the ICPs in patients with features of raised ICP undergoing supratentorial tumor resection. Administration of HTS is associated with a transient increase in serum sodium concentrations that is statistically significant but clinically insignificant and returns to normal within 48 h.
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There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]