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Review Articles

Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: A meta-analysis of randomized clinical trials*
Hooman Kamel, MD; Babak B. Navi, MD; Kazuma Nakagawa, MD; J. Claude Hemphill III, MD, MAS; Nerissa U. Ko, MD
Objectives: Randomized trials have suggested that hypertonic saline solutions may be superior to mannitol for the treatment of elevated intracranial pressure, but their impact on clinical practice has been limited, partly by their small size. We therefore combined their findings in a meta-analysis. Data Sources: We searched for relevant studies in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and ISI Web of Knowledge. Study Selection: Randomized trials were included if they directly compared equiosmolar doses of hypertonic sodium solutions to mannitol for the treatment of elevated intracranial pressure in human subjects undergoing quantitative intracranial pressure measurement. Data Extraction: Two investigators independently reviewed potentially eligible trials and extracted data using a preformed data collection sheet. Disagreements were resolved by consensus or by a third investigator if needed. We collected data on patient demographics, type of intracranial pathology, baseline intracranial pressure, osms per treatment dose, quantitative change in intracranial pressure, and prespecified adverse events. Our primary outcome was the proportion of successfully treated episodes of elevated intracranial pressure. Data Synthesis: Five trials comprising 112 patients with 184 episodes of elevated intracranial pressure met our inclusion criteria. In random-effects models, the relative risk of intracranial pressure control was 1.16 (95% confidence interval, 1.00 –1.33), and the difference in mean intracranial pressure reduction was 2.0 mm Hg (95% confidence interval, 1.6 to 5.7), with both favoring hypertonic saline over mannitol. A mild degree of heterogeneity was present among the included trials. There were no significant adverse events reported. Conclusions: We found that hypertonic saline is more effective than mannitol for the treatment of elevated intracranial pressure. Our meta-analysis is limited by the small number and size of eligible trials, but our findings suggest that hypertonic saline may be superior to the current standard of care and argue for a large, multicenter, randomized trial to definitively establish the first-line medical therapy for intracranial hypertension. (Crit Care Med 2011; 39:554 –559) KEY WORDS: intracranial hypertension; intracranial pressure; mannitol; hypertonic saline; meta-analysis; randomized controlled trial

annitol is recommended as the first-line osmotic agent for the treatment of intracranial hypertension attributable to traumatic brain injury (TBI) (1), intracerebral hemorrhage (2), malig-

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*See also p. 601. From the Department of Neurology, University of California, San Francisco, CA. Supported, in part, by the Department of Neurology, University of California, San Francisco, CA. The authors have not disclosed any potential conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s web site (www.ccmjournal.com). For information regarding this article, E-mail: hooman.kamel@ucsf.edu Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e318206b9be

nant cerebral infarction (3), subarachnoid hemorrhage (4), and acute liver failure (5). Numerous studies have shown that mannitol is effective in decreasing intracranial pressure (ICP) (6), and at least one randomized clinical trial has shown that mannitol reduces mortality compared to barbiturates in patients with elevated ICP from TBI (7). However, mannitol has many clinically important adverse effects, such as renal failure and hypovolemia (6, 8). These adverse effects of mannitol have led to increasing enthusiasm about the use of hypertonic saline formulations, which can reduce ICP without causing volume contraction and with less risk of nephrotoxicity (9 –12). Several randomized clinical trials have suggested that sodium-based hypertonic solutions may be superior to mannitol in reducing ICP (13–17), but the impact of these studies on clinical practice has

been limited, partly because of the different specific formulations used and partly because of the small size of these studies (18). Therefore, to better understand the relative efficacy of these two forms of osmotic therapy, we performed a meta-analysis of randomized clinical trials comparing hypertonic sodium solutions and mannitol for the treatment of elevated ICP. This report of our study conforms to the recommendations of the QUORUM statement on the quality of reporting for meta-analyses of randomized clinical trials (19).

MATERIALS AND METHODS
Inclusion Criteria. We included randomized clinical trials involving human subjects (without exclusions based on age, sex, or race) undergoing some method of quantitative ICP measurement (e.g., intraparenchymal monitor, external ventricular drain, lumbar drain, and others) and displaying evidence of ele-

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we included search terms for common causes of elevated ICP. 3 . hemorrhage. and age (adult vs pediatric subjects). and sex of patients. as defined in each study. a comparison of mannitol and hypertonic saline in patients with elevated ICP. 18). In other words.g.com/CCM/A199]). and 64% were men.K. 14. and compartment syndrome from extravasation. To examine the effects of this statistical assumption regarding the mean and median. Specifically.. without regard for the underlying cause. we used a random-effects model based on the method of DerSimonian and Laird. number of episodes of elevated ICP treated with a randomized allocation of a study drug. we used the Cochrane highly sensitive search strategy for MEDLINE and a similar strategy for EMBASE (21).com/CCM/A200]). If the mean change in ICP was not reported. 14. whereas hypertonic sodium solutions were effective in 88 of 95 episodes (93%. including TBI. http://links. 14.N. and Ichai et al (17) used hypertonic sodium lactate.. mean baseline ICP in each group. To ensure the inclusion of studies not specifically indexed to terms related to ICP. We expected heterogeneity among the trials from differences in hypertonic sodium formulations and subject populations. crossover treatments for episodes of elevated ICP not responsive to the initial therapy were not included. To assess for possible publication bias. because this would have precluded standardized comparison of the two drugs. 17). allocation concealment.K.) if needed. baseline mean ICP ( or 25 mm Hg. The full articles of the remaining studies were retrieved and independently reviewed by two investigators (H. In our primary analysis. see Supplementary Data File 1 [Supplemental Digital Content 1. 17. but otherwise the overall methodological quality of the included studies was fairly high. and B. We formally evaluated the quality of eligible studies using the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials (22). corresponding to a standard 50-g dose of mannitol). we calculated the pooled relative risk of ICP control with hypertonic saline compared to mannitol. studies were judged on the adequacy of the random sequence generation. Most studies included a mix of patients with TBI. hypotension. but several amplified their sample size by including multiple episodes of elevated ICP per patient (13. Eligible trials directly compared the effect on ICP of equiosmolar doses (within 20%) of hypertonic sodium and mannitol solutions. we searched for unpublished abstracts in Scopus and unreported studies in the http://clinicaltrials.) reviewed the titles and abstracts of all studies identified in this way and excluded those that were obviously irrelevant. 85%–97%). We included trials involving an unblinded or crossover design. For each trial. None of the studies reported the occurrence of any of our prespecified adverse events. and a funnel plot did not reveal visual evidence of publication bias. and subarachnoid hemorrhage (13. The average age of patients was 38 yrs ( 13 yrs). Disagreements were resolved by consensus or by a third investigator (K. Quality Assessment. especially because the main outcomes were quantified objective ICP readings. Because these statistical methods may be underpowered to detect heterogeneity. with the unit of analysis being each randomized dose of study drug administered to treat a new episode of elevated ICP. so all data were extracted from intention-to-treat analyses only. We contacted study authors for clarifications and further information as necessary. the possibility of selective outcome reporting. Battison et al (14) and Schwarz et al (13) used hypertonic sodium chloride plus starch. We excluded trials using varying doses or varying infusion times (e.10 or I2 50% (26). because this has been shown to be reasonably accurate when the sample size is approximately 25 (23). we performed sensitivity analyses by excluding such studies altogether or alternatively imputing the SD based on those of the other studies (25).g.lww. We recorded the reported frequency of the following prespecified adverse events. etc. 39. and blinding. total osms per treatment dose. RESULTS Five studies enrolling a total of 112 adult patients met our eligibility criteria (13. We expected to include trials with crossover designs and multiple treatments per patient. We did not find any potentially eligible unpublished abstracts or unreported trials. http://links. All studies were limited by the absence of blinding. as defined in each study: acute renal failure. coagulopathy.). we calculated it by subtracting the mean posttreatment ICP from the mean pretreatment ICP. we used the same strategy to calculate the weighted difference between the two treatment groups in mean ICP reduction. Among the 112 patients in the eligible trials. We complemented this by using the Related Articles function on PubMed and searching the reference lists of relevant articles. we explored pos- sible sources of heterogeneity with prespecified subgroup and meta-regression analyses based on the following categories: type of hypertonic sodium formulation (containing starch/dextran or not). intracerebral hemorrhage. and because randomeffects models may not perform as well with few studies. we used the median to represent the mean. but we did not plan to include such studies in our analysis because of concerns about methodological limitations of unpublished trials (20). age. and then calculated the SD from the p value of the difference in means within the study (24). hypertonic sodium plus lactate. Mannitol was effective in controlling elevated ICP in 69 of 89 episodes (78%. All the trials were small (the largest enrolled 40 patients). and stroke. subarachnoid hemorrhage. Statistical Analysis.gov registry. and stroke). If the change in ICP was not reported in terms of mean and SD.lww. 27) (see Supplemental Fig. we recorded the number. and the existence of other potential sources of bias. No. the Cochrane Central Register of Controlled Trials (CENTRAL). titrating drug to effect). 95% CI.vated ICP. a total of 184 episodes of intracranial hypertension were randomly treated with mannitol or a hypertonic sodium solution. significant heterogeneity was prespecified as p .N. We included trials using any formulation containing at least 3% sodium chloride or equivalent (e. because some studies used this as the treatment threshold instead of 20 mm Hg). One investigator (H. Our primary outcome was the proportion of cases in which randomized drug administration resulted in control of ICP. pulmonary edema. osms per dose ( or 300 mosm. which describes the flow diagram of search results and study selection [Supplemental Digital Content 2. starch. as long as the treatment allocation was randomized. we also performed an analysis using a fixed-effects model for comparison. therefore. 67%– 86%). We assessed for heterogeneity among studies using Cochran’s Q statistic and Higgins’ I2 statistic. Afifi et al (27) and Francony et al (18) compared mannitol to hypertonic sodium chloride. We performed an electronic search of MEDLINE.e. 1.. The pooled relative risk of ICP control using 555 Crit Care Med 2011 Vol. 95% confidence interval [CI]. Search Strategy. but crossover treatments for new recurrent episodes of elevated ICP in the same patient were allowed as long as randomization was maintained. for full details of the search strategy. stroke. To limit our search to randomized clinical trials. and the lowest mean ICP or the maximum mean change in ICP in each group within 60 mins of treatment. We used text words and medical subject heading terms to identify studies involving the study population and intervention of interest (i. Scopus. Data Extraction.) using a structured form to determine eligibility and extract data. intracerebral hemorrhage. 18. Data Sources. EMBASE. and ISI Web of Knowledge for relevant studies published in any language between January 1967 and April 2010. the completeness of outcome data. Because we expected a small number of eligible studies. type of intracranial pathology (TBI. one study exclusively consisted of patients with TBI (17) and one exclusively consisted of patients with recently resected supratentorial tumors (27) (Table 1). and we then calculated the SD of the mean difference using the reported p value. In our secondary analysis.

0% sodium chloride 5. when a fixedeffects model was applied. 0. Forest plot showing relative risk (RR) of successful control of elevated intracranial pressure. In our other prespecified subgroup analyses.8 mm Hg.1) ICP.1–3. In comparison. The weighted mean difference in ICP reduction using hypertonic saline compared to mannitol was 2. 1). Fig. p .9)a 22.276.0 mm (95% CI.8) 10% below baseline TBI (n Mannitol formulation Sodium formulation 20% 3. We did not find any eligible pediatric trials.0 mm Hg (95% CI. DISCUSSION Figure 1. and we did not have sufficient data to perform subgroup analysis based on the type of intracranial pathology.0 (20. No.36.33. p . 1.65 mosm/kg N/A N/A Decrease 5 mm Hg or absolute 20 mm Hg 19 of 27 (70%) 28 of 31 (90%) 5 (2) 8 (2) 16 of 20 (80%) 19 of 20 (95%) 13 (5) 12 (5) 14 of 18 (78%) 16 of 18 (89%) 7. I2 24% in our primary analysis).7) 11.3)a 18 mm Hg Afifi et al (27) 2003 Egypt 40 36 (6) Tumor (n 40) Francony et al (18) 2008 France 20 40 (14) TBI (n 17) Intracranial hemorrhage (n 2) Stroke (n 1) 20% 7. our point estimates did not substantially change but 556 the confidence intervals narrowed.a which are expressed as median (interquartile range). CI.036). 1. Fig.6 to 5. 3 .16 (95% CI.5–17. 25. ICP decrease denotes the maximum decrease in mean ICP (mm Hg) within 60 mins of study drug administration. 2).5 (5.3)a 10 of 14 (71%) 16 of 16 (100%) 4. hypertonic saline compared to mannitol was 1. we found that hypertonic sodium solutions are more effective than mannitol in controlling episodes of elevated ICP. dose per treatment. and the weighted mean difference in ICP reduction using hypertonic saline compared to mannitol was 2.7 mm Hg.05– 1.20 (95% CI.1 (1.6 (4.0 (18.0 (11. and one showed a statistically sigCrit Care Med 2011 Vol. ICP control denotes the proportion of episodes of elevated ICP successfully treated with a randomized dose of study medication. Study characteristics Study Study Characteristics Study year Country Subjects (n) Age (yr) Cases Battison et al (14) 2005 UK 9 Not available TBI (n 6) Subarachnoid hemorrhage (n 3) 20% 7. except ICP measurements from Battison et al. traumatic brain injury.49 mosm/kg 5. (p .5% sodium chloride hydroxyethyl starch (60 g/L) 220 mosm 257 mosm 26. intracranial pressure.5) 28.00 –1. or baseline mean ICP. p .1–26. Continuous measures are expressed as mean (SD).74 mosm/kg 1. There were too few eligible studies to perform meta-regression.007).6 (4. two of the five trials reported statistically greater quantitative ICP reduction using hypertonic sodium compared to mannitol.8)a 13. p . TBI.046. one showed a trend favoring hypertonic sodium.8. there were no clear differences in effect size among subgroups based on the type of hypertonic saline formulation. 1. one showed equivalence. We also found a trend toward greater quantitative ICP reduction in the hypertonic sodium group. Our prespecified tests indicated a mild degree of heterogeneity among trials In this meta-analysis of five randomized clinical trials.26.Table 1.45% sodium chloride 255 mosm 255 mosm 31 (6) 27 (3) 20% below baseline 10 of 10 (100%) 9 of 10 (90%) 14 (8) 10 (5) Ichai et al (17) 2009 France 34 36 (15) 34) Schwarz et al (13) 1998 Germany 9 57 (11) Stroke (n 8) Intracranial hemorrhage (n 1) 20% 7.8–11.0 (7. Individually. confidence interval.49 mosm/kg 31 (4) 31 (4) 20 mm Hg 20% Sodium lactate Mannitol dose Sodium dose Baseline ICP (mm Hg) Mannitol Sodium Definition of ICP control ICP control Mannitol Sodium ICP decrease Mannitol Sodium 1. the relative risk of ICP control favoring hypertonic saline was 1. 39.5% sodium chloride 6% dextran-70 249 mosm 250 mosm 24.

Alberts MJ. In addition to the clinical evidence reviewed. mannitol may improve microvascular cerebral blood flow (37). et al: Guidelines for the management of severe traumatic brain injury. This explanation is supported by the results of seven observational studies Crit Care Med 2011 Vol. Only one of the five trials (by Francony et al [18]) failed to show a trend favoring hypertonic sodium formulations. Figure 2. II. Our results suggest an absolute effect size of approximately 15% in favor of hypertonic saline. the balance of evidence indicates that hypertonic saline is more effective than mannitol for the treatment of intracranial hypertension. 39). Ideally. more importantly. but the latter had a longerlasting effect (35). specifically in terms of study population. also include assessment of long-term neurologic outcomes. nificant advantage to mannitol. superior to mannitol for the treatment of elevated ICP and argue for a large multicenter study comparing these two therapies. nevertheless. in our secondary analysis. hypertonic saline may be superior to mannitol in regard to brain oxygenation and cerebral hemodynamics (33). this became statistically significant when a fixed-effects model was used. there was a strong trend toward greater quantitative ICP reduction in patients treated with hypertonic saline compared to mannitol. del Zoppo G. Feldmann E. Furthermore. The lack of a uniform treatment effect among all the trials is not surprising. Broderick J. randomized human trials.ptosis (42). Circulation 2007. Our study is limited by the small number and size of eligible trials. WMD. making a standardized comparison difficult. more effective. CONCLUSIONS The need for more rigorous clinical data prompted us to perform this metaanalysis of existing randomized trials. reduce cerebrospinal fluid production (40). 175 osms for mannitol). the conflicting nature of these basic science considerations suggests that the preferred agent for the treatment of intracranial hypertension ultimately must be established through large. However. and its discordant results may be attributable to the effect of chance. In selecting our primary outcome. and a trial would require approximately 100 patients in each arm to have 80% power to detect this difference in the rate of ICP control between the two groups. Hyperosmolar therapy. weighted mean difference. Forest plot showing difference in mean quantitative reduction of intracranial pressure (mm Hg). this study was the smallest of the five included trials. they found that 7. treatment thresholds. In addition.5% sodium chloride was more effective in treating refractory intracranial hypertension. et al: Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: A guideline from the American Heart Association/American Stroke Association Stroke Council. A trial by Vialet et al (15) was not eligible because different osms per dose were used in the two treatment groups (361 osms for hypertonic saline vs. which can mask significant intragroup heterogeneity of treatment effect. Regardless. confidence interval. improve blood rheology (6. For example. and we noted no obvious methodological differences between this trial and the others that would explain this disparity. J Neurotrauma 2007. These limitations preclude a firm recommendation to preferentially use hypertonic saline as first-line therapy. While we await such a trial. A trial by Harutjunyan et al (16) did not qualify because study drugs were titrated to effect. and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. such a trial would incorporate a uniform hypertonic sodium solution and. and failure to control for clustering among patients receiving multiple doses of study drug. Connolly S. we chose each study’s clinical definition of ICP control. 116: e391– e413 3. However. there are also numerous biochemical and physiologic considerations when choosing between hypertonic saline and mannitol for the treatment of elevated ICP.2% sodium chloride plus hydroxyethyl starch was superior to mannitol in reducing ICP. Congress of Neurological Surgeons. and our prespecified subgroup analyses did not reveal an explanation for differences in effect size. but the pooled results indicate that hypertonic sodium solutions are. on average. None individually were sufficiently powered to show a difference in the proportion of episodes of elevated ICP that were successfully treated. reduce blood viscosity (38). improved cerebrospinal fluid absorption (36). but our findings indicate that hypertonic sodium solutions are. as well as their methodological differences. improved cardiac output. CI. they found that 7. 24:S14 –S20 2. because this is a more clinically relevant end point than the mean quantitative decrease in ICP. Our meta-analysis revealed only a mild degree of heterogeneity. et al: Guidelines for the early management of 557 . Adams HP Jr. well-performed. we expected heterogeneity from methodological differences among the trials. Another observational study found no significant difference between the efficacy of mannitol and hypertonic saline. Overall. promote freeradical scavenging (41). 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