Comparison of Equimolar Doses of Mannitol and Hypertonic Saline for the Treatment of Elevated Intracranial Pressure After Traumatic Brain Injury

The purpose of this meta-analysis was to compare the effectiveness of mannitol and hypertonic saline for reducing intracranial pressure (ICP) after traumatic brain injury (TBI). PubMed, Cochrane, Embase, and ISI Web of Knowledge databases were searched until July 3, 2014 using the terms intracranial hypertension, mannitol, and hypertonic saline. Randomized controlled trials and 2-arm prospective studies in which elevated ICP was present after TBI treated with mannitol or hypertonic saline were included. The primary outcome was the change of ICP from baseline to termination of the infusion, while the secondary outcomes were change from baseline to 30, 60, and 120 minutes after terminating the infusion and change of osmolarity from baseline to termination. A total 7 studies with 169 patients were included. The mean age of patients receiving mannitol ranged from 30.8 to 47 years, and for patients receiving hypertonic saline ranged from 35 to 47 years. A pooled difference in means1⁄4 1.69 (95% confidence interval [CI]: 2.95 to 0.44, P1⁄4 0.008) indicated that hypertonic saline reduced ICP more effectively than mannitol when compared from the baseline value to the last measurement after treatment. At 30 minutes after intervention, there was no difference in the mean ICP change between the groups, whereas at 60 minutes after intervention (pooled difference in means1⁄4 2.58, 95% CI: 4.37 to 0.80, P1⁄4 .005) and 120 min after intervention (pooled difference in means1⁄4 4.04, 95% CI: 6.75 to 1.32, P1⁄4 .004) hypertonic saline resulted in a significantly greater decrease in ICP. The pooled difference in means1⁄4 1.84 (95% CI: 1.64 to 5.31, P1⁄4 .301) indicated no difference in serum osmolarity between patients treated with hypertonic saline or mannitol. Hypertonic saline is more effective than mannitol for reducing ICP in cases of TBI. (Medicine 94(17):e736) D, Jing Cai, MD, and Ying-hong Hu, PhD INTRODUCTION C erebral edema and elevated intracranial pressure (ICP) are cardinal manifestations of severe brain injury in cases of traumatic brain injury (TBI), stroke (ischemic and hemorrhagic), aneurysmal subarachnoid hemorrhage, infection, and neoplasms. An elevated ICP can result in life-threatening compromised cerebral circulation and brainstem compression, and is the most common cause of death in patients with severe TBI. Hyperosmolar therapy is used to treat cerebral edema and elevated ICP, and hypertonic saline and mannitol are 2 of the commonly used agents. In brief, the osmotic agents create an osmotic gradient across an intact blood–brain barrier and thus draw water from the cerebral interstitium into the vascular space. The volume decrease in the brain reduces the ICP. Mannitol is effective at reducing ICP, and has been used for decades in the treatment of TBI. However, it may precipitate acute renal failure if serum osmolarity exceeds 320 mOsm/L, and there are concerns of elevated serum concentrations of mannitol and rebound intracranial hypertension. Concerns with the use of mannitol have led to interest in other agents. Hypertonic saline appears to be safe, and elevations of serum sodium with the use of hypertonic saline have not been associated with significant neurologic, cardiac, or renal injury. Prior meta-analyses have suggested that hypertonic saline is more effective than mannitol at reducing ICP, but have been limited by the small number and size of included trials. Thus, the purpose of this meta-analysis was to compare the effectiveness of mannitol and hypertonic saline for reducing ICP after TBI. MATERIALS AND METHODS Literature Search Strategy This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. PubMed, Cochrane, Embase, and ISI Web of Knowledge databases were searched until July 3, 2014 using combinations of the search terms: intracranial hypertension, mannitol, and hypertonic saline. The approval by an institutional review board is not required for this study because human subjects were not studied. Selection Criteria and Data Extraction Inclusion criteria were randomized controlled trial (RCT), 2-arm prospective or retrospective study; patients sustained TBI; elevated ICP; and treatment consisted of hypertonic saline or mannitol. Cohort studies, letters, comments, editorials, case reports, proceedings, and personal communications were studies that did not include patients with ly included patients with stroke or brain ied pediatric patients, and those that did www.md-journal.com | 1 Medicine Volume 94, Number 17, May 2015 not provide quantitative data with respect to the primary outcome were also excluded. Data extracted from studies that met the inclusion criteria were the name of the first author, year of publication, study design, demographic data of patients, Glasgow Coma Score (GCS), the presence of intracranial hypertension and level, osmolarity, dosage, formulation, and administration of mannitol and hypertonic saline, and outcomes. Data extraction was performed by two independent reviewers, and a third reviewer was consulted for any uncertainties. Quality Assessment The methodological quality of each study was assessed using the risk-of-bias assessment tool outlined in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) by 2 reviewers. Outcome Measures and Data Analysis The primary outcome was the mean change of ICP from baseline to the last measurement after terminating the infusion between patients treated with mannitol and hypertonic saline. The secondary outcomes were mean change of ICP from baseline to 30, 60, and 120 minutes after terminating the infusion, and the mean change of osmolarity from baseline to the last measurement after terminating the infusion between patients treated with mannitol and hypertonic saline. If data were not presented as mean and standard deviation, median, range, and the size of the sample were used to estimate the mean and variance. If median and interquartile range (IQR) were reported, it was assumed that the median of the outcome variable was equal to the mean response and the width of the interquartile range was approximately 1.35 standard deviations. The difference in means with 95% confidence intervals (CIs) were calculated for each individual study and for the pooled estimates. A x-based test of homogeneity was performed using Cochran Q statistic and I. I indicates the percentage of the total variability in effect estimates among trials due to heterogeneity rather than chance. Random-effects models of analysis were used if heterogeneity was detected (I> 50%). Otherwise, fixed-effects models were used. Pooled effects were calculated, and a 2-sided P value <.05 was considered to indicate statistical significance. Sensitivity analysis was carried out for the primary outcome using the leave-one-out approach. Publication bias was assessed by constructing funnel plots for the primary outcome and by Egger test. The absence of publication bias is indicated by the data points forming a symmetric funnel-shaped distribution, and a 1-tailed significance level P>.05 (Egger’s test). All analyses were performed using Comprehensive Meta-Analysis statistical software, version 2.0 (Biostat, Englewood, NJ). RESULTS Literature Search A flow diagram of study selection is shown in Figure 1. After initially identifying 260 articles, 244 were excluded and the full texts of 16 were reviewed. Subsequently, 9 studies were excluded, and 7 studies were included in the systematic review and meta-analysis (Table 1). Li et al Study Characteristics Characteristics of the 7 studies are summarized in Table 1, and outcomes are summarized in Tables 2 and 3. A total of 169 2 | www.md-journal.com patients were included in the 7 studies, and the mean age of patients who received mannitol ranged from 30.8 to 47 years, and for patients who received hypertonic saline ranged from 35 to 47 years. Intracranial Pressure Six of the 7 studies provided complete data with respect to ICP change from baseline to the last measurement after termination of the infusion, and were included in the meta-analysis. There was no evidence of heterogeneity (Q statistic1⁄4 7.10, I1⁄4 29.57%, P1⁄4 .213); therefore, a fixedeffects model of analysis was used. The pooled difference in means1⁄4 1.69 (95% CI: 2.95 to 0.44, P1⁄4 0.008) indicated that hypertonic saline reduced ICP more effectively than mannitol (Figure 2A). Four studies provided complete ICP data at baseline and 30 minutes after intervention. There was no evidence of heterogeneity (Q statistic1⁄4 0.44, I1⁄4 0%, P1⁄4 .932); therefore, a fixed-effects model was used. The pooled difference in means1⁄4 0.87 (95% CI: 2.57 to 0.83, P1⁄4 .316) indicated no difference in mean change of ICP between patients treated with mannitol and hypertonic saline (Figure 2A). Four studies provided complete ICP data at baseline and 60 minutes after intervention. There was no evidence of heterogeneity (Q statistic1⁄4 2.50, I1⁄4 0%, P1⁄4 .475); therefore, a fixed-effects model was used. The pooled difference in means1⁄4 2.58 (95% CI: 4.37 to 0.80, P1⁄4 .005) indicated that hypertonic saline resulted in a significantly greater decrease in ICP than mannitol (Figure 2A). Three studies provided complete ICP data at baseline and 120 minutes after intervention. There was no evidence of heterogeneity (Q statistic1⁄4 2.40, I1⁄4 16.5%, P1⁄4 .302); therefore, a fixed-effects model was used. The pooled difference in means1⁄4 4.04 (95% CI: 6.75 to 1.32, P1⁄4 .004) indicated that hypertonic saline resulted in a significantly greater decrease in ICP than mannitol (Figure 2A). Osmolarity Three studies provided complete numerical data with respect to osmolarity. There was no evidence of heterogeneity among the 3 studies (Q statistic1⁄4 1.02, I1⁄4 0%, P1⁄4 .599); therefore, a fixed-effect model of analysis was used. The pooled FIGURE 1. Flow diagram of study selection. difference in means1⁄4 1.84 (95% CI: 1.64 to 5.31, P1⁄4 .301) indicated no difference in serum osmolarity between patients treated with hypertonic saline or mannitol (Figure 2B). Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. T A B L E 1 . B a si c C h a ra ct e ri st ic s o f th e In cl u d e d S tu d ie s R ef er en ce S tu d y D es ig n P at ie n ts In te rv en ti on R ou te of A d m in is tr at io n F or m u la ti on N u m b er of P at ie n ts A ge (y ) M al e (% ) G C S at A d m is si on E p is od es of