Hypertonic saline (HTS) and mannitol are used to

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1 A Comparison of 3% Hypertonic Saline and Mannitol for Brain Relaxation During Elective Supratentorial Brain Tumor Surgery Ching-Tang Wu, MD,* Liang-Chih Chen, MD, Chang-Po Kuo, MD,* Da-Tong Ju, MD, Cecil O. Borel, MD, Chen-Hwan Cherng, MD, DMSC,* and Chih-Shung Wong, MD, PhD* BACKGROUND: In this study, we compared the effects of 3% hypertonic saline (HTS) and 20% mannitol on brain relaxation during supratentorial brain tumor surgery, intensive care unit (ICU) stays, and hospital days. METHODS: This prospective, randomized, and double-blind study included patients who were selected for elective craniotomy for supratentorial brain tumors. Patients received either 160 ml of 3% HTS (HTS group, n 122) or 150 ml of 20% mannitol infusion (M group, n 116) for 5 minutes at the start of scalp incision. The PCO 2 in arterial blood was maintained within 35 to 40 mm Hg, arterial blood pressure was controlled within baseline values 20%, and positive fluid balance was maintained intraoperatively at a rate of 2 ml/kg/h. Outcome measures included fluid input, urine output, arterial blood gases, serum sodium concentration, ICU stays, and hospital days. Surgeons assessed the condition of the brain as tight, adequate, or soft immediately after opening the dura. RESULTS: Brain relaxation conditions in the HTS group (soft/adequate/tight, n 58/43/21) were better than those observed in the M group (soft/adequate/tight, n 39/42/35; P 0.02). The levels of serum sodium were higher in the HTS group compared with the M group over time (P 0.001). The average urine output in the M group (707 ml) was higher than it was in the HTS group (596 ml) (P 0.001). There were no significant differences in fluid input, ICU stays, and hospital days between the 2 groups. CONCLUSIONS: Our results suggest that HTS provided better brain relaxation than did mannitol during elective supratentorial brain tumor surgery, whereas it did not affect ICU stays or hospital days. (Anesth Analg 2010;110:903 7) Hypertonic saline (HTS) and mannitol are used to treat intracranial hypertension. 1 5 Several prospective clinical trials that compared the effects of HTS and mannitol on intracranial pressure (ICP) suggest that HTS is at least as effective as, if not better than, mannitol in the treatment of increased ICP However, most studies included various brain pathologies, and the protocols of administration of HTS or mannitol and the osmolar load of the compounds varied among these reports. The purpose of our study was to compare the effects of the application of an equiosmolar bolus of HTS with those of mannitol on intraoperative brain relaxation (as the primary outcome) and intensive care unit (ICU) stays and hospital days (as the secondary outcomes) in patients undergoing elective craniotomy for supratentorial brain tumors. From the *Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei; Division of Anesthesiology, Kaohsiung Armed Forces General Hospital, Kaohsiung; Department of Neurosurgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; and Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. Accepted for publication November 8, Supported by grants from the Department of Health (DOH95-PA-1053B) of Taiwan, Republic of China. Address correspondence and reprint requests to Dr. Ching-Tang Wu, Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, # 325, Section 2, Chenggung Rd., Neihu 114, Taipei, Taiwan. Address to wuchingtang@msn.com. Copyright 2010 International Anesthesia Research Society DOI: /ANE.0b013e3181cb3f8b METHODS After obtaining the approval of the IRB of the National Defense Medical Center (Taipei, Taiwan) and written informed consent from patients, we performed a power calculation to determine the ideal sample size before initiation of the study. A minimum of 106 patients was required in each group to detect a decrease in the incidence of tight-brain condition from 36% to 18%, with a power of 80% and a confidence interval of 95%. To compensate for potential dropouts, we enrolled a minimum of 116 patients in each group. Two hundred thirty-eight patients who were scheduled to undergo elective craniotomy for supratentorial brain tumors were enrolled in this prospective, randomized, and double-blind study. The data were collected between January 2005 and January Exclusion criteria were age 18 years, Glasgow Coma Scale score 13, ASA physical status IV V, signs of increased ICP, perioperative hypo- or hypernatremia (serum sodium 135 or 150 meq/l, respectively), history of treatment with any hyperosmotic fluids (HTS or mannitol) within the 24 hours preceding the surgery, and history of congestive heart failure or severe renal function impairment. All patients received 10 mg dexamethasone IV every 6 hours for 48 hours before brain tumor resection. After randomization using sealed envelopes, patients were assigned to receive IV administration of equiosmolar hyperosmotic fluids, either 160 ml of 3% HTS (HTS group) or 150 ml of 20% mannitol (M group) for 5 minutes using an infusion pump and a central line at the time of scalp incision. The surgeons and anesthesiologists were blinded to the identity of the agents under study. March 2010 Volume 110 Number

2 Hypertonic Saline and Brain Relaxation Anesthetic Management General anesthesia was induced with 2% lidocaine (1.5 mg/kg), fentanyl (2 g/kg), propofol (2 mg/kg), and rocuronium (0.6 mg/kg) using a peripheral IV line. In addition to standard monitoring, we placed a radial arterial line, a central venous pressure (CVP) catheter, and a train-of-four stimulator. Anesthetic maintenance included 1% sevoflurane in oxygen combined with IV infusion of propofol (dose range, 3 4 mg/kg/h) and an IV bolus of fentanyl or cisatracurium, if necessary, which were administered at the attending anesthesiologist s discretion. ETco 2 monitors were calibrated preoperatively and deviation values between Pco 2 in arterial blood (Paco 2 ) and ETco 2 were recorded. We adjusted Paco 2 between 35 and 40 mm Hg according to the values of ETco 2. Heart rate and arterial blood pressure (ABP) values were kept within baseline values 20% using fentanyl and labetalol and by adjusting the dosage of propofol. Although a CVP catheter was placed in each patient, we managed the fluid input according mainly to urine output (i.e., 100 ml urine output using 100 ml of 0.9% saline or Ringer solution supplement). A positive fluid balance was maintained at a rate of 2 ml/kg/h, in addition to replacement of urine output with 0.9% saline or Ringer solution, in turn, throughout the procedure. Blood loss was compensated using 10% pentastarch at the ratio of 1:1. The criteria for the performance of blood transfusion were hemoglobin 10 mg/dl or the presence of other clinical indications. Estimation of Dural Tension and Cerebral Swelling Surgeons blinded to the anesthetic techniques assessed the degree of brain relaxation using a 3-point scale of tight (1), adequate (2), and soft (3) immediately after opening the dura. In cases in which surgeons were not satisfied with the degree of brain relaxation after surgical appraisal, another bolus of the study fluid was administered, unless contraindicated, and, if necessary, hyperventilation was initiated to maintain Paco 2 values between 30 and 35 mm Hg. All patients were tracheally extubated when fully awake and were then transferred to the neurologic ICU. The time to transfer to a general ward and discharge were decided by the attending neurologist, who was also blinded to the study. The variables measured included (1) amount of study agent administered, (2) perioperative fluid input and urine output, (3) hourly recording of laboratory data, including blood gases and serum sodium concentration, and (4) ICU stays and hospital days. Statistical Analyses Data are presented as the mean sd or as the median with ranges. One-way analysis of variance with repeated measures and paired Student t test were used for the analysis of data within each group (fluid input, urine output, blood loss, and hospital days). Differences between the HTS and M groups were analyzed using a 2 test (demographic variables), a Mann-Whitney U test (brain relaxation scores), and an unpaired Student t test with Bonferroni correction for multiple measurements (fluid input, urine output, blood loss, and hospital days). A multivariate analysis of Table 1. Patient Characteristics Group HTS (n 122) Group M (n 116) P Age (y) 56 (18 80) 54 (18 80) 0.23 Male/female 56/66 56/ Height (cm) 162 ( ) 162 ( ) 0.67 Weight (kg) 57.9 (43 78) 58.7 (42 76) 0.80 ASA physical status II/III 26/96 28/ Data are presented as median and range. HTS hypertonic saline; M mannitol. variance was used for the comparison of changes in serum sodium over time between the groups. P 0.05 was considered significant. RESULTS There were no significant differences between the 2 groups regarding age, sex, severity of illness, anesthetic time, and operation time (Tables 1 and 2). The hemodynamics, Paco 2, ETco 2, and CVP levels were not significantly different between the groups (data not shown). The number of brain conditions classified as soft, adequate, and tight in the HTS group was 58, 43, and 21, respectively, whereas it was 39, 42, and 35, respectively, in the M group. Brain relaxation was significantly better in the HTS group compared with the M group (P 0.02). Twenty-one patients in the HTS group and 35 patients in the M group required the administration of additional fluids for brain relaxation (P 0.02) (Table 2). There was no significant difference of additional hyperventilation (Paco 2 maintained within mm Hg) between the 2 groups (8 vs 15; P 0.13) (Table 2). Compared with mannitol, HTS caused an increase in serum sodium concentration over time (P 0.001, Fig. 1). Urine output was higher in the M group (707 ml; range, ml) compared with the HTS group (596 ml; range, ml; P 0.001). There were no significant differences in fluid input before opening of the dura, total fluid input, ICU stays, and hospital days between the 2 groups (Table 2). DISCUSSION In our randomized study, we demonstrated that (1) 3% HTS provided a more satisfactory brain relaxation than did mannitol; (2) 3% HTS was associated with a significantly higher level of serum sodium compared with mannitol; (3) compared with 3% HTS, mannitol had a more prominent diuretic effect; and (4) ICU stays and hospital days were similar between the 2 groups after elective supratentorial brain tumor surgery. The physical effects of HTS and mannitol on the brain of patients with normal ICP have been investigated. 11,13 Gemma et al. 11 and De Vivo et al. 13 reported that HTS and mannitol both provided satisfactory brain relaxation in patients undergoing elective craniotomy. These 2 study populations with normal ICP were similar to ours; however, different neurosurgical procedures were involved and nonequiosmolar HTS or mannitol was delivered. 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 ANESTHESIA & ANALGESIA

3 Table 2. Surgical and Anesthetic Data Group HTS (n 122) Group M (n 116) P Brain condition (soft/adequate/tight) 58/43/21 39/42/ Anesthetic time (min) 299 ( ) 286 ( ) 0.19 Operation time (min) 268 ( ) 257 ( ) 0.29 Fluid input before opening of the dural (ml) % Saline % Pentastarch PRBC % Saline Mannitol Total fluids input (ml) % Saline Ringer s solution % Pentastarch PRBC 0 (0 150) 0 (0 150) % Saline 160 ( ) 0 Mannitol ( ) Total urine output (ml) 596 ( ) 707 ( ) Number of patients required additional doses of 3% saline or mannitol (n) Number of patients required additional hyperventilation (n) ICU stays (d) 1 (1 3) 1 (1 3) 0.71 Hospital days (d) 6 (5 8) 6 (5 8) 0.86 Data are presented as number, median (range), or mean (SD). Brain condition was subjectively evaluated by the neurosurgeon. HTS hypertonic saline; M mannitol; PRBC packed red blood cell; ICU intensive care unit. Figure 1. Sodium (Na) concentration in arterial blood. Hypertonic saline (HTS) administration caused an increase in serum Na concentration at points 0, 1, 2, 3, 4, and 5 compared with the baseline (point 1) and mannitol (#P 0.001). In the presence of mannitol, Na concentration decreased at points 0, 1, and 2 compared with point 1 (*P 0.001). Point 1 indicates the onset of hyperosmotic solution infusion; point 0 indicates the time of dural opening; point 1 indicates 1 hour after the end of the infusion; points 2, 3, and 4 indicate 2, 3, and 4 hours after the end of the infusion; and point 5 indicates the end of surgery. M mannitol. human and animal studies. 1 4,14 17 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 bloodbrain barrier (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 of 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 addition, a lower RC contributes to lower incidence of rebound cerebral edema. 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. 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. 12 The increase in serum sodium stimulates the release of antidiuretic hormones, leading to the absorption of free water from the kidney, 18 which may explain the lower diuretic effect of HTS compared with mannitol. In addition, Rozet et al. 12 reported that mannitol had a more prominent diuretic effect and a less positive or even negative fluid balance, which was associated with an increase in blood lactate over time, whereas no changes in blood lactate were observed after HTS administration. The negative fluid balance induced by mannitol suggests that the increase in lactate concentration may be secondary to effective hypovolemia. Because hypovolemia is considered detrimental after brain injury, HTS solutions have gained renewed interest and, recently, are administered more frequently in neurocritically ill patients Together with the hyperosmotic mechanism, the improved blood rheology with shrinkage of erythrocytes, the decreased cerebrospinal fluid production, and the antiinflammatory and other lesser properties associated with both HTS and mannitol are believed to play a role in their March 2010 Volume 110 Number

4 Hypertonic Saline and Brain Relaxation therapeutic action on healthy and injured brains. 23,26 However, it has become popular to view HTS as having some advantages over mannitol. Oddo et al. 27 examined the effects of mannitol (25%, 0.75 g/kg) and HTS (7.5%, 250 ml) on brain tissue oxygen tension in 12 patients with refractory intracranial hypertension. They showed that if these patients exhibited a poor response to previous mannitol treatment, the administration of 7.5% HTS as the second-tier therapy was associated with a significant increase in brain oxygenation and improved cerebral and systemic hemodynamics. Heimann et al. 28 showed HTS improved cerebral blood flow and reduced the area of infarction by using a laser Doppler approach in a rat cerebral ischemia model. Moreover, Taylor et al. 29 used a near-infrared spectrophotometer to show that cerebral oxygenation was restored more rapidly in the HTS-treated group in a pediatric animal model of head injury and hemorrhagic shock. The comparison of HTS and mannitol revealed that the former seems to favor ICP reduction, brain circulation, cerebral oxygenation, and hemodynamic stability. In addition, HTS was associated with more pronounced increase in osmolarity 30 and decrease in ICP, 30,31 which improve brain swelling and cerebral perfusion and attenuate the progression of secondary brain injury. Therefore, it was reasonable to presume that the HTS group would exhibit improved outcomes. However, we did not detect any significant differences in ICU stays and hospital days between the 2 groups. In this study, surgery was performed by 1 of the 3 senior neurosurgeons. Although serious complications were not observed, the prognosis of brain tumor surgery was 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 stays and hospital days in the 2 groups were similar, perhaps because (1) these 2 study outcomes were affected mainly by the factors described above, rather than by the different effects of HTS and mannitol on brain relaxation; (2) significant differences may have been present mainly at the cellular level or at the cognitive function level, which was beyond the scope of our study; (3) even though HTS yielded a greater effect on brain relaxation, it is very important to note that a reduction in brain volume does not necessarily translate into a better cerebral outcome 32 ; and (4) the median ICU stays and hospital days was just 1 and 6 days, respectively. Thus, it is possible that the obvious effects of HTS would be apparent in patients who were more seriously ill. Throughout the procedure, we maintained Paco 2 between 35 and 40 mm Hg and ABP within baseline values 20% to avoid the effect of CO 2 and ABP on brain bulk until assessment by the surgeon. It is possible that ABP fluctuations were manipulated by the blinded anesthesiologist; however, this is unlikely because no specific hemodynamic pattern emerged before the surgical appraisal. We did not measure ICP routinely during elective supratentorial brain tumor surgery in clinical practice. Although brain relaxation can be influenced by ICP, patients with signs of increased ICP were excluded from the study. HTS solutions have evolved as an alternative to mannitol or may be used to manage otherwise refractory intracranial hypertension. Caution is advised for high osmolar fluid loads because they are associated with an increased risk of the potentially deleterious consequences of hypernatremia or may induce osmotic BBB opening, with possible harmful extravasation of the hypertonic solution into the brain tissue. 32 However, if administered via an appropriate route and at an appropriate dose, it is no more dangerous than other similar drugs, including mannitol. 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