A prospective, randomized, double blind study to compare the effects of equiosmolar solutions of 3% hypertonic saline and 20% mannitol on reduction of brain-bulk during elective craniotomy for supratentorial brain tumor resection.

AIMS: The aim of the study was to compare the effect of mannitol (M) and hypertonic saline (HTS) on brain relaxation and electrolyte balance. SETTINGS AND
DESIGN: Prospective, randomized, double-blind study. SUBJECTS AND METHODS: A total of 114 patients with American Society of Anesthesiologists status II and III, scheduled to undergo craniotomy for supratentorial brain tumor resection were enrolled. Patients received 5 ml/kg 20% mannitol (n = 56) or 3% HTS (n = 58) at the start of scalp incision. Hemodynamics, fluid balance and electrolytes, were measured at 0, 15, 30, and 60 min and 6 h after infusion. Intensive Care Unit (ICU) stay between the two groups was also recorded. The surgeon assessed brain relaxation on a four-point scale (1 = Relaxed, 2 = Satisfactory, 3 = Firm, 4 = Bulging). Appropriate statistical tests were used for comparison; P < 0.05 was considered significant.
RESULTS: Brain relaxation conditions in the HTS group (relaxed/satisfactory/firm/bulging, n = 28/20/5/3) were better than those observed in the M group (relaxed/satisfactory/firm/bulging, n = 17/21/11/9). The levels of serum sodium were higher in the HTS group (P < 0.001). The average urine output was higher in the M group (5.50 ± 0.75 L) than in the HTS group (4.38 ± 0.72 L) (P < 0.005). There was no significant difference in fluid input, ICU stay, and hospital days between the two groups.
CONCLUSION: We concluded that HTS provided better brain relaxation than mannitol during elective supratentorial brain tumor surgery, without affecting ICU and hospital stay.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Cerebral relaxation during intracranial surgery has been considered a neuroprotective measure as it can reduce surgical compression, local hypoperfusion, and cerebral ischemia.[1] Administration of osmotherapy at the onset of craniotomy before opening the dura mater is one of the interventions used to produce a cerebral relaxation in elective neurosurgeries. Osmolality is the primary determinant of water movement through the intact blood-brain barrier (BBB), and it is predictable. If we increase serum osmolality, normal brain tissue would dehydrate, and the cerebral volume, as well as the intracranial pressure (ICP), would be reduced.[2] Mannitol has become the traditional basis of hyperosmolar therapy.[34] However, it can be associated with severe adverse effects such as intravascular volume depletion, rebound ICP elevation, and renal failure.[5] Although it also has potential side effects, hypertonic saline solutions (HS) have gained renewed interest as an alternate therapy and recently have been used in neurosurgical patients.[6] Several clinical studies comparing the effects of mannitol and HS on ICP have suggested that HS is as effective as mannitol if not better for treating intracranial hypertension.[78] With this background, the present study was conducted to compare the effects of an equiosmolar bolus of HS with mannitol on intraoperative brain relaxation in patients undergoing elective craniotomy for supratentorial brain surgery.

SUBJECTS AND METHODS

After Institutional Ethical Committee approval, 114 patients American Society of Anesthesiologists II and III, >18 years of either sex, scheduled to undergo elective craniotomy for supratentorial brain tumor resection were included in this study. Exclusion criteria were history of unstable angina or myocardial infarction within past 6 months, congestive cardiac failure, Glasgow coma score <13, uncontrolled diabetes, severe renal impairment, preoperative hyponatremia (serum sodium <130 meq/L) or hypernatremia (serum sodium >150 meq/L), treatment with mannitol or hypertonic saline (HTS) during previous 24 h. The study protocol was explained to all the patients and written informed consent taken from them.

No premedication was used. In the operating room, in addition to the standard monitoring, arterial and central venous catheterization was done for continuous measurement of arterial and central venous pressures (CVP). Anesthesia was induced with fentanyl 2 mcg/kg, propofol 2 mg/kg and vecuronium bromide 0.1 mg/kg body weight. Anesthesia was maintained with isoflurane (0.5-1.0 MAC) with oxygen - nitrous oxide mixture and incremental doses of vecuronium bromide as per train of four ratio. Patients were mechanically ventilated to maintain a partial pressure of carbon dioxide between 30 and 35 mmHg. After randomization using sealed, envelopes patients received either mannitol or HTS via central line at the time of scalp incision for 15 min for intraoperative brain relaxation. Patients were divided into two groups as follows: Group I (HTS group): Received 5 ml/kg of 3% HTS (Osmolarity: 1024 mOsm/l). Group II (M group): Received 5 ml/kg of 20% mannitol (Osmolarity: 1098 mOsm/l). The surgeons and anesthesiologists were blinded to the agent under study. Positive fluid balance was maintained with 2 ml/kg/h, in addition to replacement of urine output with 0.9% normal saline. Brain relaxation was assessed by the surgeon immediately after opening the dura on a 4 point scale as follows: 1 = Adequately relaxed, 2 = Satisfactorily relaxed, 3 = Firm brain, 4 = Bulging brain. Scores 1 and 2 were taken as acceptable brain relaxation scores, while scores 3 and 4 as unacceptable brain relaxation scores. If the surgeon was not satisfied with the degree of brain relaxation on dural opening, a second bolus of 5 ml/kg of same study drug was given to provide relaxation for surgical access. All the procedures involved same team.

Following variables were measured: Hemodynamic parameters including arterial blood pressure (systolic and diastolic) and CVP, perioperative fluid balance, urine output, arterial blood gases, and electrolytes. All the variables were measured and recorded before infusion (T0) and after administration of study drug at 15 min (T15), 30 min (T30), 60 min (T60) and hourly up to 6 h (T360) after infusion. Urine output was recorded every hour. All the patients were extubated at the end of surgical procedure when fully awake and transferred to surgical Intensive Care Unit (ICU) for postoperative care.

Data thus obtained was analyzed statistically using analysis of variance and Student's t-test for fluid input, hemodynamic variables and urine output, Chi-square test for demographic variables and Mann–Whitney test for brain relaxation scores between the two groups. Data were presented as mean ± standard deviation P < 0.05 was considered as statistically significant.

RESULTS

The difference in age, weight, severity of illness, and sex between two groups was comparable [Table 1]. The hemodynamics, PaCO2, and CVP levels were not significantly different between the two groups. In our study, the number of patients with different brain relaxation scores, were adequately relaxed (28), satisfactorily relaxed (20), firm (5) and bulging (3) in group I and (17), (21), (11), and (9) in group II respectively with P = 0.024 showing that HTS provided better brain relaxation than mannitol [Table 2]. Twenty patients in-group II required additional dose of the drug as compared to 8 patients in-group I, which was found statistically significant (P = 0.0120). It was observed in our study that group I was associated with significantly higher levels of serum sodium (sustained for 6 h) with peak serum sodium concentration observed at T30, while in group II an initial decrease at T15 (133.26 ± 2.7 meq/L) followed by stepwise increase in serum sodium, was observed after infusion of study drug [Figure 1]. There was significant but transient decrease in potassium at T15 (3.10 ± 0.29; P = 0.002) after infusion of HTS (group I). In contrast, mannitol (group II) caused a stepwise increase of potassium over time [Figure 2]. The difference between serum potassium only at T15 in group I and group II was found statistically significant (P < 0.05).

Table 1

Demographic data of the groups

Table 2

Brain relaxation scores between two groups

Figure 1

Comparison of serum sodium concentration in group I and group II at different time intervals

Figure 2

Comparison of serum potassium concentration in group I and group II at different time intervals

Fluid input after 6 h was 7.041 ± 0.85 L and 7.219 ± 0.96 L in the group I and group II respectively. The difference between fluid input at different time intervals in two groups was statistically insignificant (P > 0.05). Urine output after 6 h was 4.38 ± 0.72 L and 5.50 ± 0.75 L in the group I and group II respectively, which was statistically significant (P = 0.000). Total difference between two groups was 1.22 L at 6 h. Mean ICU stay was statistically insignificant between the two groups [Table 3].

Table 3

Surgical and anesthetic data

DISCUSSION

One of the important goals of anesthetic management for patients undergoing craniotomy is to provide a relaxed brain for the surgeon to operate on. This allows easy surgical manipulations and causes less damage to the normal brain tissue. This in turn, results in less secondary injury to the brain, which improves the patient's neurologic outcome. A raised ICP results in a tense brain during the intraoperative period. Medical management of cerebral edema and elevated ICP using osmotherapy is a critical component of perioperative care in neurosurgical practice. Several studies comparing the effects of mannitol and HTS on ICP and intraoperative brain relaxation have been conducted.[910]

In our randomized study, we demonstrated that 3% HTS provided a more satisfactory brain relaxation than mannitol; but was associated with a significantly higher level of serum sodium compared to mannitol. Compared to 3% HTS, mannitol had a more prominent diuretic effect. However, ICU stay, and hospital stay was similar between the two groups after elective supratentorial brain tumor surgery.

Administration of HTS or mannitol increases serum sodium concentration or osmolality and decreases ICP and brain water content in noninjured brain areas, as shown in human and animal studies.[111213] The principal mechanism underlying these effects is the induction of a water shift from brain tissues to the intravascular space by the hyperosmolarity of HTS and mannitol because the BBB is impermeable to sodium and mannitol. The effectiveness of the hyperosmolar solute depends on its “reflection coefficient” (RC), which determines the relative impermeability of an intact BBB to the solute. An RC of 1 means an absolutely impermeable solute and an RC 0 means an ideally permeable solute. HTS may present a theoretical advantage over mannitol because sodium has a higher osmotic RC than does mannitol (1.0 vs. 0.9). A lower solute leakage may evoke a greater increase in serum osmolality, and a higher transendothelial osmotic gradient in the vascular compartment may lead to increased brain water extraction into the intravascular space. In this regard, our data revealed a more effective brain-bulk reduction associated with HTS versus mannitol, which is consistent with the classic theory of hyperosmotic therapy. This finding correlates with study of Wu et al.[14] who observed that brain relaxation conditions in the HTS group (soft/adequate/tight, n = 58/43/21) were better than those observed in M group (soft/adequate/tight, n = 39/42/35; P = 0.02). De Vivo et al. and Gemma et al. reported that both HTS and mannitol provided satisfactory brain relaxation in patients undergoing elective craniotomy. These two study populations with normal ICP were similar to ours; however, different neurosurgical procedures were involved, and nonequiosmolar HTS or mannitol was delivered. Rozet et al. however observed similar effects on brain relaxation using equiosmolar solutions of mannitol and HTS. This could be because of varied neurosurgical pathologies and small sample size in their study.

Hyperkalemia after mannitol administration has been reported,[15] but the exact mechanism of this phenomenon is unknown. One of the explanation suggests a cellular potassium efflux with the water, as a result of hyperosmolar condition.[16] The development of hypokalemia with HTS can be explained as a compensatory mechanism to maintain electrical neutrality in circumstances of induced hyperchloremic acidosis associated with the infusion.[1718] Our study showed that 3% HTS was associated with significantly higher levels of serum sodium and a decreased diuretic effect compared with mannitol, which is compatible with the results of Rozet et al. The increase in serum sodium stimulates the release of antidiuretic hormones, leading to the absorption of free water from the kidney, which may explain the lower diuretic effect of HTS compared with mannitol. In addition, Rozet et al. reported that mannitol had a more prominent diuretic effect and a less positive or even negative fluid balance leading to effective hypovolemia. Because hypovolemia is considered detrimental after brain injury,[1920] HTS solutions have gained renewed interest and recently, are administered more frequently in neurocritically ill patients.[2122] The comparison of HTS and mannitol revealed that the former seems to favor ICP reduction, brain circulation, cerebral oxygenation, and hemodynamic stability.[2324] In addition, HTS was associated with more pronounced increase in Osmolarity[25] and decrease in ICP, which improve brain swelling and cerebral perfusion and attenuate the progression of secondary brain injury.[26] Therefore, it was reasonable to presume that the HTS group would exhibit improved outcomes. However, we did not detect any significant differences in ICU and hospital stay between the two groups.

Although serious complications were not observed, the prognosis of brain tumor surgery is influenced by many factors, including the size and the location of the tumor, the severity of the adjacent tissue damage, the residual function after tumor excision, and the immune or inflammatory responses to the procedure. The results of ICU and hospital stay in the two groups were similar, perhaps mainly because the outcome depends on other factors as described above.[5] Throughout the procedure, we maintained PaCO2 between 30 and 35 mm Hg and mean arterial blood pressure within 20% of baseline values, to avoid the effect of CO2 and MAP on brain-bulk until assessment by the surgeon.

Although the study groups were well matched for most characteristics, we did not match various tumor-related factors such as the tumor size, histology, perifocal edema, and midline shift, which could independently affect the brain relaxation. The study did exclude patients with Glasgow Coma Scale score <13 and patients with signs of increased ICP, but it is still possible to have patients without signs of increased ICP but with variable intracranial compliance. Bedford et al.[27] have shown a positive correlation between the amount of preoperative brain edema surrounding the tumor and subsequent increases in ICP greater than baseline values. We did not measure ICP routinely during elective supratentorial brain tumor surgery in clinical practice. These can be considered as limitations of our study.

Our results suggest that HTS provided better brain relaxation than did mannitol during elective supratentorial brain tumor surgery, whereas it did not affect ICU and hospital stay.