Mannitol versus Hypertonic Saline for Management of Elevated Intracranial Pressure Jerry Altshuler, PharmD; Diana Esaian, PharmD, BCPS

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1 Mannitol versus Hypertonic Saline for Management of Elevated Intracranial Pressure Jerry Altshuler, PharmD; Diana Esaian, PharmD, BCPS The intracranial compartment consists of predominantly brain parenchyma and a relatively small amount of cerebrospinal fluid and plasma. This compartment is a fixed volume of approximately ml. 1 Increases in volume of one of the aforementioned intracranial components from insults such as subarachnoid hemorrhage, intracerebral hemorrhage, brain tumors, traumatic brain injury (TBI), and hepatic encephalopathy can potentially raise the intracranial pressure (ICP). Elevation of ICP is associated with significant morbidity and mortality. Increased ICP can damage brain parenchyma, potentiate hydrocephalus and cause herniation. ICP is the difference between the cerebral perfusion pressure (CPP) and mean arterial pressure (MAP). CPP acts as a surrogate for the cerebral blood flow (CBF). Maintaining ICP under 20 mm Hg and CPP of 60 mm Hg appears to be a crucial intervention after TBI where autoregulation of CBF is often compromised. In addition to intubation (which can allow for hyperventilation), sedation, CPP optimization (MAP control) and surgical decompression, treatment of intracranial hypertension relies heavily on reducing ICP by using an osmotically active agent. 2 Traditionally, mannitol has been recommended as the agent of choice to decrease ICP; conversely, hypertonic saline solution (HTSS) is an osmotically active alternative with a myriad of potential benefits. Several studies have implicated that HTSS is comparable and potentially superior to mannitol. 3, 4 Both agents seem to be reasonable choices for decreasing intracranial pressure. Therefore, the aim of this review is to compare the advantages and disadvantages of these drugs. Mannitol is a 182-molar weight, six-carbon alcohol that is synthesized from dextrose reduction. It is available as 25% vials (1375 mosm/l) and 20% bags (1100 mosm/l). Mannitol is renally cleared with approximately 7% tubular reabsorption. In the cerebrovasculature, mannitol draws water out of the brain via osmotic pressure while enhancing cerebral blood flow. 5 These properties make mannitol a reasonable agent to decrease ICP. Several studies have demonstrated the effectiveness of mannitol in controlling intracranial hypertension. 6, 7 Interestingly, mannitol decreases ICP within minutes of administration despite osmotic effects being absent until minutes after administration. 8 Mannitol use is not without its disadvantages, however. It can cause acute tubular necrosis, hypernatremia, hypokalemia, and hypotension due to increased loss of electrolyte poor water via osmotic diuresis. 9 Conversely, renal insufficiency or large mannitol doses can lead to intravascular drug accumulation, and consequently hyponatremia and hyperkalemia due to osmotically induced influx of water and potassium from the intracellular space. 10 Additionally, the reflection coefficient (a measure of a solute s ability to cross a membrane) of mannitol is 0.9, suggesting that mannitol can cross the blood-brain barrier and pull fluid back into the intracranial space. This may explain the

2 rebound effect seen with ICP after mannitol use, especially after repeat 11, 12 administration. HTSS is available in a plethora of standard concentrations including: 3% (1027 mosm/l), 5% (1711 mosm/l) and 23.4% (8008 mosm/l). Certain concentrations contain sodium acetate in a 1:1 ratio to mitigate hyperchloremic acidosis. HTSS works in a similar fashion to mannitol by establishing a hypertonic intravasculature and thus promoting osmotic outward flow of water from brain cells. The reflection coefficient of HTSS is 1, ensuring that it does not pass through an intact blood-brain barrier. 13 The primary concern with HTSS is osmotic demyelination, which may occur from a large and acute increase in serum sodium. A 1998 article by Schwarz et al studied nine stroke patients who experienced 30 episodes of ICP crisis. 3 A crisis was defined as an ICP greater than 25 mm Hg or pupillary abnormality. Patients were randomized to receive equiosmolar doses of either 100 ml of 7.5% hypertonic saline hydroxyethyl starch (HS-HES) solution or 40 g of mannitol. The two agents were alternated for repeat treatments. The primary endpoint was a 10% decrease in ICP below baseline or cessation of pupillary response. All 16 episodes that were treated with HS-HES elicited a successful response, while 10 of 14 episodes treated with mannitol achieved a 10% decrease in ICP. The maximum ICP decrease with HS-HES was 11.4 mm Hg, and this occurred at 25 minutes post-infusion; the maximum ICP decrease with mannitol use was 6.4 mm Hg, and this occurred at 45 minutes. The mannitol group consistently observed elevations in CPP with a mean increase of 19.2% from baseline (P <0.01). This same effect was not seen with HS-HES. It was noted, however, that ICP decreased to a greater degree and more rapidly in patients treated with HS-HES compared to mannitol (mean decrease of 11 mm Hg vs. 5.3 mm Hg at 25 minutes). Appreciable adverse events were not seen in either group. Another study published in 2003 by Vialet et al compared 2 m L/kg of 7.5% HTSS vs. 2 ml/kg of 20% mannitol in 20 trauma patients. 4 Primary study variables included the number of intracranial hypertension (defined as an ICP >25 mm Hg) episodes per day and their duration. Failure rate was defined as persistently elevated ICP despite two consecutive administrations of the same agent. The mean number of daily episodes of intracranial hypertension was significantly higher in the mannitol group compared to HTSS (13.3 vs. 6.9). Additionally, the duration of episodes was longer in the mannitol group (131 vs. 67 min, P <0.01). Most importantly, the rate of failure was 1 of 10 patients in the HTSS group compared to 7 of 10 patients in the mannitol group (P <0.01). It is noteworthy that the doses used in each group were not osmotically equivalent (5.13 mosm/kg of HTSS vs. 2.2 mosm/kg of mannitol). A study by Francony et al compared 20% mannitol solution to an iso-osmolar amount of 7.45% HTSS in 20 patients with TBI and stroke who had ICP elevations above 20 mm Hg. 14 The primary endpoints were the change in ICP and CPP within the first 2 hours of

3 study drug administration. The mannitol group experienced a mean ICP decrease of 45% at 60 minutes and 32% at 2 hours, while the HTSS group had ICP reductions of 35% at 60 minutes and 23% at 2 hours. Interestingly, only the mannitol group had increases in CPP, which was attributed by the authors to the potentially positive effects on blood rheology demonstrated by mannitol. The increase in CPP, however, did not improve overall brain oxygenation; indeed, a major limitation of this study is that all included patients had baseline CPP values >60 mm Hg with brain oxygenation values within normal limits. Another study conducted by Sakellaridis et al looked at 29 patients with severe head injury experiencing 199 hypertensive events (ICP >20 mm Hg). 15 Patients were randomized to receive equiosmolar doses of 20% mannitol or 15% HTSS and alternating these agents with successive hypertensive episodes. The difference in ICP reduction between the two groups was not different, with a mean reduction of 7.96 mm Hg in the mannitol group and 8.43 mm Hg in the HTSS group (P = 0.586). Despite several small clinical trials suggesting utility in using HTSS; mannitol has remained the agent of choice for treating elevated ICP in most centers. Given that the few available prospective clinical trials have enrolled only a modest number of patients, Kamel et al conducted a meta-analysis in 2011 that examined the use of HTSS vs. mannitol. 16 This study examined five small, nonblinded, prospective randomized controlled trials. The majority of these trials consisted of patients with a mixture of TBI, stroke, intracerebral hemorrhage and subarachnoid hemorrhage. A total of 184 intracranial hypertensive events were noted among the 112 patients in all five trials. Mannitol successfully controlled intracranial hypertension in 78% (95% confidence interval [CI]: 67%-86%) while HTSS was effective in 93% of cases (95% CI: 85%-97%). The weighted mean change in ICP in patients receiving HTSS compared to mannitol was 2 mm Hg (95% CI, mm Hg, P = 0.036). Of the five individual trials involved in the meta-analysis, two noted greater ICP reduction with HTSS; one showed a trend toward superiority with HTSS; one noted no statistical difference; and one demonstrated statistically significant improvement with mannitol. While this meta-analysis does combine five small trials with a modest degree of heterogeneity, it suffers from having a small total number of patients. Additionally, variations in ICP control definitions, different underlying disease states and failure to report adverse events are all limitations of this study. Mannitol is a hyperosmolar agent that has seen much use over the years for ICP reduction in patients with elevated ICP. HTSS is an alternative to mannitol and may potentially be a superior agent. The studies reviewed above provide some data that the efficacy of HTSS, in terms of both rate and extent of fluid removal from brain cells, may exceed that of mannitol. In addition to absolute reduction in ICP, beneficial extra-osmotic effects of both agents should be taken into consideration. Mannitol s ability to decrease blood viscosity causes an increase in CPP and CBF. The propensity to scavenge free radicals is also an appealing 17, 18 attribute. The extra-osmotic effects associated with HTSS include decreased CSF production, enhanced oxygen delivery to the brain, and potential modulation

4 of vasopressin and atrial natriuretic peptide. 19 The lack of significant adverse events, especially the potential for nephrotoxicity, makes HTSS an attractive option for certain patients, especially given that many critically ill patients will experience renal dysfunction. However, patients who are hypernatremic may not be good candidates for HTSS or those lacking central venous access due to concern for vesicant extravasation when using the more concentrated formulations. Finally, hypotensive patients should not receive mannitol due to its potential blood pressure-lowering effects, while HTSS may beneficially raise pressures in these patients. When utilizing osmotic therapy with either drug, target serum osmolality should be between mosm/l. Serum sodium should be targeted between 145 and155 meq/l when HTSS is employed. 20 A large scale prospective clinical trial using equiosmolar doses and assessing clinical outcomes is necessary to determine if a true comparative benefit exists with either of these agents. In the meantime, clinicians should utilize the agent that they are most experienced with, while taking into account potential patient factors that may necessitate the need for individualized therapy. References 1) Kaye AH, Laws E. Brain Tumors: An Encyclopedic Approach. 2 nd ed. New York, NY: Churchill Livingstone, ) Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24:S-1 S-95. 3) Schwarz S, Schwab S, Bertram M, Aschoff A, Hacke W. Effects of hypertonic saline hydroxyethyl starch solution and mannitol in patients with increased intracranial pressure after stroke. Stroke. 1998;29: ) Vialet R, Albanèse J, Thomachot L, et al. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2mL/kg 7.5% saline is more effective than 2 ml/kg 20% mannitol. Crit Care Med. 2003;31: ) Nissenson A, Raymond W, Kleeman C. Mannitol. West J Med. 1979;131: ) James HE. Methodology for the control of intracranial pressure with hypertonic mannitol. Acta Neurochir (Wien). 1980;51: ) McGraw CP, Howard G. Effect of mannitol on increased intracranial pressure. Neurosurgery. 1983;13: ) Barry KG, Berman AR. The acute effect of the intravenous infusion of mannitol on blood and plasma volume. N Engl J Med. 1961;264: ) Gipstein RM, Boyle JD. Hypernatremia complicating prolonged mannitol diuresis. N Engl J Med. 1965;272: ) Aviram A, Pfau A, Czaczkes JW, Ullmann TD. Hyperosmolality with hyponatremia, caused by inappropriate administration of mannitol. Am J Med. 1967;42: ) Rockwald GL, Solid C, Paredes-Andrade, et al. Hypertonic saline and its effect on intracranial pressure, cerebral perfusion pressure, and brain tissue oxygenation. Neurosurgery. 2009;65: ) Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992;77: ) Bhardwaj A, Ulatowski JA. Cerebral edema: hypertonic saline solutions. Curr Treat Options Neurol. 1999;1: ) Francony G, Fauvage B, Falcon D, et al. Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial hypertension. Crit Care Med. 2008;36:

5 15) Sakellaridis N, Pavlou E, Karatzas, et al. Comparison of mannitol and hypertonic saline in the treatment of severe brain injuries. J Neurosurg. 2011;114: ) Kamel H, Navi BB, Nakagawa K, Hemphill JC 3rd, Ko NU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39: ) Rosner MJ, Coley I. Cerebral perfusion pressure: a hemodynamic mechanism of mannitol and the postmannitol hemogram. Neurosurgery. 1987;21: ) Schrot RJ, Muizelaar JP. Mannitol in acute traumatic brain injury. Lancet. 2002;359: ) Chang Y, Chen TY, Chen CH, et al. Plasma arginine-vasopressin following experimental stroke: effect of osmotherapy. J Appl Physiol. 2006;100: ) Larive LL, Rhoney DH, Parker D, et al. Introducing hypertonic saline for cerebral edema: an academic center experience. Neurocrit Care. 2004;1: