Hypertonic Saline and Mannitol Therapy in Critical Care Neurology

Transcription

1 Analytic Reviews Hypertonic Saline and Mannitol Therapy in Critical Care Neurology Journal of Intensive Care Medicine 28(1) 3-11 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Holly E. Hinson, MD 1, Deborah Stein, MD, MPH, FACS 2, and Kevin N. Sheth, MD 3 Abstract Osmotic agents play a vital role in the reduction of elevated intracranial pressure and treatment of cerebral edema in Neurologic critical care. Both mannitol and hypertonic saline reduce cerebral edema in many clinical syndromes, yet there is controversy over agent selection, timing, and dosing regimens. Despite the lack of randomized, controlled trials, our knowledge base on the appropriate clinical use of osmotic agents continues to expand. This review will summarize the evidence for the use of mannitol and hypertonic saline in a variety of disease states causing cerebral edema, as well as outlining monitoring and safety considerations. Keywords mannitol, hypertonic saline, osmotic therapy, cerebral edema Received July 7, 2010, and in revised form September 20, Accepted for publication October 12, Introduction Although osmotic agents have been utilized to reduce cerebral edema for nearly 5 decades, significant controversy regarding choice of agent and dosing exists. While a variety of agents have been investigated including hypertonic urea, glycerol, and sorbitol, 1-3 this review will focus on the 2 main agents used in adult clinical practice today: mannitol and hypertonic saline (HS). This review will summarize the evidence for the use of these 2 agents in a variety of disease states causing cerebral edema, as well as outlining monitoring and safety considerations. Pharmacologic Properties Mannitol Mannitol has long been recognized for its ability to reduce intracranial pressure (ICP) in animals and entered the clinical realm in 1960s. 4 It is a freely filtered, nonmetabolized solute that decreases the reabsorption of water and, to a lesser extent, sodium, across the renal tubule, creating diuresis. Mannitol works in a biphasic fashion to reduce ICP. Initially, it alters blood dynamics (rheology), specifically by reducing the viscosity of blood. Mannitol has been shown to reduce blood viscosity by reducing red cell rigidity, thereby easing the passage of the red cell through small blood vessels independent of hematocrit. 5 This effect disappears 4 hours after administration. Mannitol also increases intravascular volume due to increased plasma osmolality, as well as increasing cardiac output. 6 In response to reduced viscosity and intravascular volume expansion, there is compensatory cerebral vasoconstriction when autoregulatory pathways are intact. 7 Thismaybeexplained by Ohm s law in which flow (Q) ¼ pressure difference (DP)/resistence (R). If autoregulation is impaired, reduction in ICP may be modest or absent. Of note, increased cerebral bloodflow(cbf)maybeseeninareasofinjuredbrainwith impaired autoregulation, largely due to decreased blood viscosity. The second phase of ICP reduction occurs as mannitol extracts water from the cerebral extracellular space into the intravascular compartment via the osmotic gradient between blood and brain. It is thought that this requires an intact blood-brain barrier to form an osmotic membrane. Controversy exists regarding where the volume is removed from injured or uninjured tissue. It appears that both injured and uninjured tissues contribute to the volume of water lost, 8,9 particularly in the models of both diffuse and focal traumatic brain injury 1 Neurosciences Critical Care, Johns Hopkins Medical Institutions, Baltimore, MD, USA 2 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA 3 Division of Stroke and Neuro-Critical Care, Departments of Neurology, Surgery, Neurosurgery, and Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA Corresponding Author: Kevin N. Sheth, Division of Neuro-Critical Care & Stroke, Neurology/Neurosurgery/Emergency Med/Anesthesiology, University of Maryland School of Medicine, University of Maryland Medical Center, Adams Cowley Shock Trauma Center, 110 South Paca Street, 3rd floor, Baltimore, MD 21201, USA ksheth@som.umaryland.edu

2 4 Journal of Intensive Care Medicine 28(1) Table 1. Comparison of Osmotic Agents Solution Concentration Sodium Concentration (meq/l) Osmolarity (mosm/l) Ringer s lactate Mannitol 20% n/a 1098 Mannitol 25% n/a (TBI). Uninjured brain is the main source of water extraction, especially with repeat dosing in ischemic stroke. 10,11 Mannitol is generally dosed 0.25 to 1.0 g/kg. 12 The reduction of serum sodium occurs as its resorption across the renal tubule is inhibited by mannitol. Serum sodium may drop from 9 to 13 meq/l depending on the patient s total body water content. 13 Mannitol s excretion is largely governed by the glomerular filtration rate (GFR); however, in patients with high amounts of total body water (eg, ascites, severe peripheral edema) mannitol will be cleared more slowly than predicted from GFR alone. Assuming normal GFR and total body water, plasma mannitol concentration should fall to 10% or less of the initial equilibrium dose after 4 hours, and may be redosed thereafter. 13 Hypertonic Saline Hypertonic saline gained popularity initially as a volume expander in acute resuscitation, particularly in hemorrhagic shock. 14 Investigators noted that among patients sustaining TBI, there was an improved survival rate, 15 which was attributed to reduction in cerebral edema and validated in animal models. 16,17 As a result, HS evolved over time as an alternative to mannitol in treating cerebral edema. Hypertonic saline has been shown in animal models to produce a biphasic reduction in ICP, first by way of rheology followed by osmotic activity across the blood-brain barrier. 18,19 Hypertonic saline has the additional theoretical benefit of being less permeable than mannitol across the blood-brain barrier due to its higher reflection coefficient. As a consequence, the theoretical potential for water to follow the solute into the brain worsening cerebral edema is reduced. 20 The majority of inquiry regarding HS has occurred in TBI, although literature in other forms of cerebral edema exists. Table 1 compares the concentration and osmolality of several commonly utilized formulations. As there is no universally agreed-upon concentration or schedule for administering HS, comparison between studies is difficult. Additionally, higher concentrations of HS, particularly 23.4% saline, must be given via central venous access, making its administration less feasible for patients without a central line catheter. Continuous infusions as well as bolus dosing of varying concentrations of HS have been investigated as alternatives to mannitol for reducing cerebral edema, especially in TBI and postoperatively. However, the improvements in cerebral edema seen in TBI have not been observed in patients with ischemic or hemorrhagic stroke to the same degree, possibly suggesting a more pronounced effect on vasogenic edema than cytotoxic edema. Hypertonic saline seems to be safe when given in continuous infusion as an alternative to normal saline. Froelich et al retrospectively compared patients with varying severe neurologic injuries, 107 of which received continuous infusions of 3% HS, while 80 received normal saline. Continuous hypertonic therapy was not associated with an elevated risk of deep-vein thrombosis, rate of infection, or renal failure compared to the normal saline group. 21 In contrast, others have found continuous hypertonic therapy to be possibly detrimental. Qureshi et al found that continuous infusions of HS (2% or 3%) did not lessen the need for cerebral edema interventions. In fact, patients receiving continuous HS had higher in-hospital mortality than patients receiving normal saline. 22 These findings lead the authors to recommend bolus dosing for cerebral edema reduction, which is the preferred practice in our center. Clinical Applications Mannitol Versus HS Limited head-to-head comparisons exist comparing the efficacy of mannitol to HS in reduction of ICP. Table 2 lists 5 recent prospective trials comparing the 2 agents. Vialet et al prospectively examined a series of patients with severe TBI and elevated ICP, comparing 7.5% saline with 20% mannitol. 25 The authors found their patient cohort had fewer episodes and shorter durations of elevated ICP with 2 ml/kg of 7.5% saline compared with 2 ml/kg of body weight of 20% mannitol. Additionally, episodes of elevated ICP requiring external ventricular drainage and total CSF drained were fewer in the saline group. 25 However, it is critical to assure that osmolar loads are dosed in a similar fashion to make a valid comparison. In the Vialet study, the mannitol group received a much smaller osmolar load, potentially driving the better result in the saline group. 25 Francony et al compared the effectiveness of a single eqimolar infusion of 20% mannitol with 7.45% HS for ICP reduction in a group of patients with a variety of neurologic injuries. They found that both agents were equally effective at reducing ICP. 24 However, only mannitol increased cerebral perfusion pressure (CPP) and CBF velocities. Based on these results, the authors recommend mannitol to be first line in patients with poor cerebral perfusion, and HS to be considered in patients with hypovolemia or hyponatremia. 24 The authors allude to an important clinical concern when choosing mannitol: vigilant attention to volume status is essential in order to not disrupt hemodynamics. If not addressed, this point can be a potential confounder in studies comparing mannitol with HS. Most recently, Ichai et al compared 3% sodium lactate with 20% mannitol, both dosed at 1.5 ml/kg in a population of patients with TBI. 23 Sodium lactate

3 Hinson et al 5 Table 2. Recent Prospective Trials Comparing Mannitol and Hypertonic Saline Author (Year) Type of Prospective Trial Agent Condition(s) Treated Number of Patients? Outcome Ichai et al Randomized (2009) 23 controlled Francony et al Randomized (2008) 24 controlled Battison Randomized (2005) 25 controlled Harutjunyan Randomized (2005) 26 controlled Vialet et al Randomized (2003) 27 controlled 3% sodium lactate vs 20% mannitol TBI 34 HS>Mannitol for #ICP, "GOS 7.5% HS vs 20% mannitol TBI þ Stroke 20 Both #ICP similarly 20 ml 20% mannitol vs 100 ml 7.5% HS dextran TBI þ SAH 9 HS > mannitol for #ICP 7.2% HS þ 6% HES vs 15% mannitol neurosurgical 40 HS > mannitol for #ICP patients 7.5% HS vs 20% mannitol TBI 20 HS > Mannitol for reducing elevated ICP episodes Abbreviations: CBF, cerebral blood flow; CPP, cerebral profusion pressure; GOS, Glascow Outcome Score; HES, hydroxyethyl starch; HS, hypertonic saline; ICP, intracranial pressure; NS, normal saline; TBI, traumatic brain injury; SAH, subarchnoid hemorrhage Table 3. Avoiding Adverse Effects of Osmotic Agents Complication Mannitol Hypertonic Saline Renal Failure Avoid continuous infusion, repeat high dosing Avoid prolonged hypernatremia >160 meq/l Rebound Allow clearance prior to repeat dosing Allow clearance prior to repeat dosing Metabolic Acidosis n/a Reduce chloride in admixture Hypokalemia n/a Add potassium to fluids Hypovolemia Concurrent volume resuscitation n/a was chosen as opposed to sodium chloride because the authors hypothesized that lactate might provide an advantage as a fuel for the brain under ischemic-reperfusion injury based on animal studies. Sodium lactate appeared superior in reducing ICP. The group receiving sodium lactate (either as primary therapy or as rescue after mannitol) had improved 1-year Glascow Outcome Scores compared to mannitol alone. 23 Kerwin et al retrospectively analyzed 22 patients with severe TBI who received either mannitol (15 to 75 g) or 30 ml of 23.4% HS for control of ICP >20 sustained for more than 5 minutes. The investigators observed significantly greater drop in ICP in the HS group in comparison to the mannitol group, leading them to conclude HS is more efficacious in reducing elevated ICP in TBI. 28 Unfortunately, the authors do not explain how the dosing of mannitol was determined (ie, a weight-based protocol), making it unclear if patients in the mannitol group were underdosed, receiving as little as 15 g in some instances. Traumatic Brain Injury Hyperosmolar agents role in neurologic injury is probably best understood in TBI, despite the fact that the evidence even in TBI ranges from class II to III. Several insights have been gained about mannitol in this population. Continuous infusion seems to be no better, if not worse, than bolus dosing. Mannitol becomes less effective with repeat dosing. Fast infusion seems to be best. Mannitol works best when autoregulation is intact. Lastly, mannitol consistently improves MAP, CPP, and CBF while lowering ICP More recently, HS has come to fore as an alternative to mannitol in TBI. Initially, continuous infusions of hyertonic saline were investigated. Qureshi et al found that a continuous infusion of 3% saline exerted a beneficial effect on ICP as well as improving lateral displacement of brain due to edema in patients with head injury, spontaneous intracranial hemorrhage (ICH) or postoperatively (after tumor resection or aneurysm clipping). 31 Like mannitol, bolus dosing of HS has shown more promise than continuous infusions for ICP management. 22 Bolus dosing for both agents might be more effective than continuous osmotic agents because continuous infusions of osmotic agents allow more time for the reestablishment of a new osmotic set point, such that the intracellular and extracellular compartments reequilibrate. No further water extraction can occur once this reequilibration occurs. Several case series have shown the effectiveness of boluses of HS for the reduction of ICP in TBI, both as an alternative and as an adjuvant to mannitol. 27,33-35 Bolus dosing regimens vary within the literature. Some authors advocate the use of 2 ml/kg of 7.5% 27 for the control of elevated ICP, while others have used 250 ml boluses of 3% 36 or 30 ml of 23.4%. 37 To date, there are no direct comparison studies between these dosing regimens. Hypertonic saline also appears to increase levels of brain tissue oxygenation (PbtO 2 ) and improve hemodynamics (higher CPP and cardiac output) when used as a Tier II therapy after mannitol administration for elevated ICP. Mannitol had no measurable effect on PbtO 2 in this study. 38 Again, these results should be interpreted with caution as equi-osmolar doses of each agent were not used. The HS group received a larger osmolar load (250 ml of 7.5% saline versus 0.75 g/kg of 25% mannitol;

4 6 Journal of Intensive Care Medicine 28(1) Table 1). There is also a suggestion that use of HS may improve biomarker profiles. Baker et al measured levels of S100B, neuron-specific enolase (NSE), and myelin basic protein in patients with severe TBI receiving either normal saline or 7.5% HS with 6% dextran for resuscitation, as opposed to cerebral edema. They found the lowest levels of these biomarkers in survivors resuscitated with HS; whereas the highest levels were seen in nonsurvivors. The link between these biomarkers and survival benefit has not yet been definitively shown. 39 As of 2007, the Brain Trauma Foundation Guidelines do not provide guidance on administration of either mannitol or HS for elevated ICP in TBI other than to indicate that both agents may lower ICP. 40 Ischemic Stroke Unlike TBI, controversy exists regarding the utility of hyperosmolar agents in ischemic stroke. First, the lack of intact bloodbrain barrier in ischemic stroke is worrisome, based on the fear that osmotic agents may leak across the compromised membrane bringing water with the solute. This phenomenon has been reported in animals, but may not apply to humans. 41 Second, mannitol seems to reduce the water content of the uninjured hemisphere, 11 which could worsen midline shift if present. To address these concerns, Manno et al examined a group of patients with complete middle cerebral artery (MCA) infarctions with cerebral edema and administered boluses of mannitol. They found that a single, large dose of mannitol (1.5 g/kg of body weight) did not worsen midline shift nor precipitate neurologic decline in the first hour after administration. 9 From a global outcomes perspective, a large retrospective observational study failed to find any effect of routine mannitol use on outcome at 1 month or 1 year. Of greater concern, depending on the variables entered into the authors regression model, mannitol appeared either to have no effect or to be harmful, rendering the authors unable to make any recommendation on the use of mannitol in ischemic stroke. 42 However, it is difficult to interpret these results as the treatment groups were not homogenous enough to be directly comparable, and routine mannitol use is not a common clinical practice its use usually being reserved for malignant cerebral edema. The literature does suggest bolus dosing of mannitol and HS can reduce ICP, but long-term outcomes in these studies were not addressed. 43,44 It may be appropriate not to address long-term outcomes, as patients requiring osmotic therapy for cerebral edema are usually critically ill. Critical illness entails many confounders affecting outcome such as ICU-acquired infections, requiring large numbers of patients to account for these confounders. Thus, ICP may be the more appropriate measure of efficacy. Continuous infusions of osmotic agents have shown less promise than bolus dosing. Bhardwaj et al found hypertonic agents might actually increase infarct volume. Utilizing an MCA occlusion model of stroke in rats, the investigators initiated osmolar therapy with 20% mannitol, 0.9% normal saline, 3% HS, or 7.5% HS at the onset of reperfusion. The group observed that continuous infusion hypertonic therapy initiated at the onset of reperfusion did not reduce infarct volume, thus may not represent an effective resuscitation strategy after ischemic stroke. It should be noted, that reperfusion time in humans is rarely available as a clinical parameter, thus caution should be employed when generalizing to humans. Surprisingly, the group randomized to 7.5% saline had a statistically significant increase in infarct volume over the other groups, causing the authors to caution its use in ischemic stroke. 45 Indeed, there has been no randomized, controlled trial addressing the use of mannitol or HS in ischemic stroke. In the absence of definitive evidence in humans, mannitol rescue therapy for malignant cerebral edema is the most common clinical practice. The American Stroke Association guidelines advise treatment of stroke-related edema and elevated ICP with mannitol as a bridge to more definitive therapy, such as decompressive craniectomy. 46 Subarchnoid Hemorrhage Both mannitol and HS significantly lower ICP in the animal model of subarchnoid hemorrhage (SAH). 47,48 A recent Norwegian study compared 30-minute infusions of 2 ml/kg of 7.2% HS or 0.9% saline (placebo) and measured ICP in stable SAH patients. The group observed a reduction in ICP of 3 mm Hg on average compared with 0.3 mm Hg in the placebo group, as well as an increase in CPP of 5.6 mm Hg compared with negligible change in CPP in the placebo group. The authors favored HS over mannitol in the SAH patient population due to the risks of diuresis-induced hypovolemia and the inherent risks of vasospasm. Additionally, the authors hypothesize that SAH patients might be more suitable for the osmotic effect of HS given a relatively intact blood-brain barrier. 49 Cerebral blood flow was of particular interest to Tseng et al. Their group showed that infusions of 23.5% HS not only reduced ICP but also increased CBF as evidenced by continuous transcranial dopplar and Xenon-enhanced computed tomography scans. Patients with the greatest increases in CBF in response to HS seemed to also have the most favorable outcomes as measured by discharge modified Rankin scores. 50 Intracerebral Hemorrhage Investigation of ICP management in intracerebral hemorrhage with osmotic agents is less robust than in other disease states like TBI. From the scant human clinical trials, it appears that scheduled, low dose mannitol (100 ml of 20% dosed every 4 hours) did not improve outcome in ICH patients or change CBF. 51,52 While no clinical trials of HS in the setting of ICH have been conducted, animal models suggest bolus dosing of 23.4% HS reverses transtentorial herniation and restores regional CBF. 53 In the same animal model, Quereshi et al also compared bolus 20% mannitol, bolus 23.4% HS, and continuous 3% HS. While all 3 groups showed an initial drop in ICP values, the investigators noted that only in the 3% group did the animals have sustained lower ICP. 54 This observation

5 Hinson et al 7 represents one of the few accounts in the literature of continuous osmotic therapy being superior to bolus dosing. This may be related to the continuous HS group benefiting from longer term intravascular volume expansion in the intracranial vasculature. Studies comparing bolus doing versus continuous infusions of lower concentration HS (2%-3%) are needed to resolve this issue. Liver Failure Cerebral edema may occur as a consequence of acute, fulminant liver failure. The presumed mechanism of cerebral edema relates to ammonia and glutamine causing cytotoxic injury combined with cerebral vasodilation from the loss of autoregulation. 55,56 Although the definitive therapy for fulminant hepatic failure is liver transplantation, the cerebral edema may be imminently life-threatening. In the 1980s, mannitol proved to be more effective than dexamethasone for reducing cerebral edema and improving outcome in liver failure. 57 More recently, interest has shifted to HS. Murphy et al induced moderate hypernatremia ( mmol/l) with a 24-hour infusion of 30% saline at 10 ml/hour in a group of liver failure patients with acute liver failure and Grade III or IV encephalopathy, and measured ICP. The group found that moderate hypernatremia along with the standard of care interventions significantly reduced ICP from baseline levels when compared with standard of care alone. Standard of care was provided to both patient groups, and included standardized ventilation management, head of bed elevation, ICP monitoring, N-acetylcystine aministration, hemodynamic monitoring with intervention for hypotension, enteral feeding, prophylactic antibiotics, and hemoglobin goals. 58 Transtentorial Herniation Mannitol, in combination with hyperventilation, has been shown to reverse transtentorial herniation in a cohort of 28 patients with a variety of underlying illnesses causing cerebral edema (including neoplasm, ICH, TBI, and ischemic stroke). 59 Hypertonic saline has also shown promise in reversing transtentorial brain herniation. A retrospective analysis of boluses (30-60 ml) of 23.4% HS reversed 75% of clinical herniation events in a cohort of patients with a variety of neurologic illnesses. 60 Monitoring Intracranial Pressure Hyperosmolar agents are frequently used to reduce ICP and/or reverse brain herniation events. Thus, it is recommended to have an ICP monitor in place to aid titration. Serum Sodium Osmolarity Generally, fluid balance should be monitored closely as mannitol may cause significant diuresis, while HS expands intravascular volume. Serum sodium concentrations and plasma osmolality are usually measured in a serial fashion after the administration of either HS or mannitol. Target serum sodium and osmolality values are controversial, but clinicians often strive for serum sodium concentrations of 150 to 160 meq/l and plasma osmolality between 300 and 320 mosm. 32 In general, an infusion of 1mL/kgof3% saline will raise the serum sodium by approximately 1 meq/l, regardless of baseline serum sodium concentration. 61 The literature suggests an increased risk of acute renal failure and metabolic acidosis when plasma osmolality >320 mosm, 12,30 however, this threshold is not absolute. 62 Diringer and Zazulia explain well in their review article, Osmotic Therapy Fact and Fiction, 62 that the value of 320 mosm was arrived at in patients receiving continuous, high-dose mannitol infusions ( g/kg per h). None of the patients in this study developed renal failure with a serum osmolality below 400 mosm. 63 In fact, a serum sodium of 160 meq/l and a plasma osmolality of 340 mosm might be a safe upper limit. 64 Osmolar Gap Unfortunately, a test for serum mannitol concentration is not commercially available. Despite its frequent clinical use, serum osmolality is a poor surrogate for serum mannitol concentrations. 65 To surmount this issue, some authors have advocated the use of osmolar gap (OG) as a method of monitoring mannitol concentrations to avoid complications such as renal failure. Osmolar gap is the difference between osmolality and osmolarity, which is used to detect the presence of unmeasured osmoles such as mannitol. 62 If the OG falls within the normal range (varying by formula and patient population), Garcia-Morales et al assert a patient has sufficiently cleared the mannitol, and may be redosed. 66 It has been suggested that maintaining an OG below 55 mmol/kg of H 2 O will help to prevent renal failure. 67 OG may be calculated by several different formulas; Diringer et al report utilizing 1.86 (Na þ K) þ (blood urea nitrogen/2.8) þ (glucose/18) þ 10 provided the best correlation to measured mannitol levels. 62 Complications Renal Failure Of particular interest is avoiding renal failure. Mannitol may become nephrotoxic by several mechanisms, including dosedependent vasoconstriction of the renal artery and intravascular volume depletion from osmotic diuresis. 68,69 In one study, the mean total dose of mannitol that precipitated acute renal failure in healthy kidneys was g over 2 to 5 days. 70 There is an association between prolonged hypernatremia (serum sodium concentration >160 meq/l) and oliguric acute renal failure observed in burn patients receiving HS as resuscitation fluid. 71 Observations of renal failure associated with HS in neurological patients is limited; 72,73 however, close monitoring of renal function is advised. Patients that already require intermittent or continuous renal replacement pose a special challenge to

6 8 Journal of Intensive Care Medicine 28(1) the use of osmotic agents. If mannitol is to be used when renal failure is already present, the smallest effective dose possible should be used (consider 0.5 g/kg). Use of hemodialysis to remove mannitol will expedite the half-life of the drug to 6 hours versus 5 or more days with GFR <50 ml/min. With regard to sodium balance, the standard sodium concentration of dialysate is 140 meq/l. Serum sodium levels will trend toward 140 meq/l as dialysis is applied, particularly for continuous renal replacement therapy (CRRT). 74 In the authors experience, frequent redosing of HS is often needed to maintain hypernatremic goals. Osmotic Demyelinating Syndrome Osmotic demyelinating syndrome or more specifically central pontine myelinolysis (CPM) may occur when sodium levels are rapidly increased with HS, causing demyelination of white matter in the CNS or specifically in the pons. Patients are most at risk when hyponateremia exists at baseline. To date, there are no case reports of CPM occurring after the administration of HS for elevated ICP 60 nor has CPM been reported in any of the trials using HS for elevated ICP. 72,73 Rebound Phenomenon After exposure to osmotic agents, ICP may precipitously rise back to an elevated level after an initial response. This is termed the rebound phenomenon and occurs particularly after mannitol administration. Previously rebound was feared as a consequence of the osmotic agent leaking into injured tissue across a damaged blood-brain barrier, and pulling water with it, promoting swelling in the injured area. However, observations of mannitol exiting the brain down its concentration gradient make this explanation less compelling. 62 Rebound is more likely related to osmotic compensation within the central nervous system, allowing for increased intracellular concentrations of electrolytes. Repeated administration of osmotic agents, especially in the setting of poor CNS compliance where small volemic changes result in dramatic changes in ICP, promote the rebound phenomenon. 75 Additionally, repeat dosing or continuous infusions of these agents without time allotted for the osmotic agent to clear might also contribute to this phenomenon. Metabolic Acidosis Hypertonic saline inhibits the resorption of bicarbonate from the proximal renal tubules. It may also produce hyperchloremic metabolic acidosis from the large amount of chloride delivered in the fluid. One possible solution to this problem is to change the fluid admixture to 50:50 sodium chloride-sodium acetate. 76 Hypokalemia Hypokalemia might also be encountered as the kidney exchanges potassium for sodium in the distal tubule. Addition of potassium to maintenance fluids may correct this. Conclusion Nearly a century after mannitol was noted to reduce cerebral edema, osmotic agents including mannitol still play an important role in the medical management of both cerebral edema and elevated ICP. Despite the lack of randomized, controlled trials, our knowledge base on the appropriate clinical use of osmotic agents continues to expand. While not definitively superior to mannitol, HS shows promise in not only reducing ICP but also in reversing neurologic deterioration and improving hemodynamics. Future work will further define agent selection and dosing regimen. The disease state as well as the type of edema encountered (vasogenic versus cytotoxic) will likely guide agent selection as clinical practice evolves. Authors Note KNS is supported by an American Academy of Neurology Clinical Research Award Declaration of Conflicting Interests The authors declared no potential conflicts of interests with respect to the authorship and/or publication of this article. 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