Neurocritical Care - The Medical University of South...

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Eelco F.M. Wijdicks, MD

Volume 1 • Number 2 • 2004 • ISSN 1541–6933 A Journal of Acute and Emergency Care

Neurocritical Care

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Original Article

AbstractThis review examines the available data on the use of osmotic agents inpatients with head injury and ischemic stroke, summarizes the physio-logical effects of osmotic agents, and presents the leading hypothesesregarding the mechanism by which they reduce ICP. Finally, it addressesthe validity of the following commonly held beliefs: mannitol accumulatesin injured brain; mannitol shrinks only normal brain and can increase mid-line shift; osmolality can be used to monitor mannitol administration; man-nitol should be not be administered if osmolality is > 320 mOsm; andhypertonic saline is equally effective as mannitol.

Key Words: Mannitol; hypertonic saline; head injury; ischemic stroke;intracranial pressure.

219

Osmotic Therapy

Fact and Fiction

Michael N. Diringer1,2* and Allyson R. Zazulia2

1Neurology/Neurosurgery Intensive Care Unit and 2Stroke Research Center, Department of Neurology,Washington University School of Medicine, St. Louis, MO

*Correspondence andreprint requests to: Michael Diringer, MD,Department of Neurology,Campus Box 8111, 660 S.Euclid Avenue, St. Louis,MO 63110. E-mail:[email protected].

Neurocritical CareCopyright © 2004 Humana Press Inc. All rights of any nature whatsoever are reserved.ISSN 1541-6933/04/2:219–234

Humana Press

IntroductionOsmotic therapy has been a cornerstone in the management of patients

with elevated intracranial pressure (ICP) since the early 1960s, yet its usehas remained controversial and poorly understood. Additionally, thereare a number of widely accepted tenets about its effects and limitationson its use, only some of which appear to be substantiated.

An ideal osmotic agent does not cross the cell membrane, thus pro-moting movement of water from the intracellular to the extracellular com-partment. As the fluid moves into the vascular space and is carried awayby the blood, the tissue shrinks. Urea, which crosses the cell membrane,

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is not an effective osmotic agent. Mannitol, onthe other hand, is an ideal osmotic agent thatneither crosses the cell membrane nor the intactblood-brain barrier (BBB). Therefore, in thebrain, it remains in the vascular compartmentwhere it can extract both intracellular and inter-stitial water.

Mannitol can cross damaged BBB, though,raising concern about the potential for it to accu-mulate within injured brain to cause an increasein cerebral edema (1) and, in the presence of uni-lateral lesions, an increase in midline shift (2).Hypertonic saline (HS) is being promoted as anosmotic agent in large part as a result of theseconcerns (3–6). However, HS may lack other fea-tures of mannitol that are thought to contributeto its therapeutic effects; mannitol is a free rad-ical scavenger (7) and inhibits programmed celldeath (8).

Physiological Effects of OsmoticTherapyPhysiological responses to the use of osmotic

agents were first detailed by Weed andMcKibben in 1919 (9). It was not until 1962, how-ever, that the first clinical use of mannitol wasdescribed (10).

Osmotic Effects If two solutions are separated by a membrane

permeable to water but impermeable to thesolutes, osmotic equilibrium is maintained bymovement of water from the solution with lowerosmolality to the one with higher osmolality.Thus, osmotic equilibrium is maintainedbetween the intra- and extracellular compart-ments of the body by free movement of wateracross the cell membrane. Increasing the osmo-lality of the extracellular compartment byadministering a hypertonic solution will resultin an influx of water from the intracellular com-partment.

The extracellular compartment is furtherdivided into the intravascular and interstitialcompartments separated by the capillaryendothelium. The capillary endothelium is per-meable to water, except in the brain where it issomewhat limited by the BBB.

The permeability of the intracellular andendothelial membranes to water and differentsolutes varies. For example mannitol easilycrosses peripheral but not central nervous sys-tem capillary endothelium. Thus the tonicity orosmotic effectiveness of a solution depends onthe osmotic gradient created, the osmotic reflec-tion coefficient (ranging from 0 to 1) of the mem-brane for that solute, and the hydraulicconductivity of the membrane. Of note, the braincapillaries have a relatively low hydraulic con-ductivity (11,12).

Mannitol and saline differ in terms of theirosmotic reflection coefficients across the BBB.Because the BBB is essentially impermeable tomannitol, the drug is restricted to the vascularcompartment in the brain. The BBB has a high-er osmotic reflection coefficient for sodium andchloride (13), so saline crosses into the intersti-tial space, but is excluded from the intracellu-lar compartment (11,12,14).

It is important to note that in many patho-logical states the integrity of the BBB is dis-rupted, resulting in increased permeability tosolutes (increased osmotic reflection coefficient)as well as increased hydraulic conductivity.These changes occur to different degrees is dif-ferent pathological states (15,16).

Brain Adaptation When water moves out of the intracellular

and interstitial spaces, the brain shrinks (17).This effect is only temporary, however (18,19).Within a few hours, levels of intracellular elec-trolytes and organic osmoles (some of whichhave not been identified and are thus referredto as “idiogenic osmoles” (17)) increase (20). Asa result, cell size is restored to normal despitethe hyperosmolar state. There are important clin-ical implications to this phenomenon: rapid cor-rection of the hyperosmolar state causes aninflux of water into the intracellular space andcan result in rebound cerebral edema (21).

Hemodynamic Effects The hemodynamic effects of osmotic agents

are an important consideration in their clinicaluse. Movement of water into the extracellular

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and thus intravascular compartments produceshemodilution and increases blood volume (22),cardiac output, and blood pressure (23). Thereis concern that in patients with poor cardiacfunction, volume expansion will precipitate con-gestive heart failure. Fortunately, when givento a group of patients with poor cardiac func-tion, mannitol was well tolerated (24), probablybecause of its rapid excretion in the urine. Themajor complications of mannitol use are hypo-volemia and hypotension resulting from its largeuncorrected urine output. On the other hand,HS is not a diuretic; rather, it is an excellent vol-ume expander that may have an advantage inthe early phase of head injury where hypov-olemia may occur (25).

Mannitol lowers blood viscosity through bothhemodilution and a decrease in the volume,rigidity, and cohesiveness of red blood cellmembranes, which reduces their mechanicalresistance (26). HS appears to have similar effects(27,28).

Pharmacokinetics

Mannitol is excreted unchanged in the urine.Its distribution and elimination follow a two-compartment model (29,30). Distribution is veryrapid, with a half-life of approximately 0.16hours. Elimination half-life is 0.5–2.5 hours fortypical clinical doses (0.25 to 1.5 g/kg bodyweight) (30). The most important determinateof mannitol clearance is renal function (31).

It is widely accepted that mannitol does notcross the BBB (11,12,14). Yet, under normal con-ditions, labeled mannitol enters the cere-brospinal fluid (CSF) of experimental animals.Peak concentrations are an order of magnitudeless than plasma levels (32), raising the ques-tion of the clinical relevance of this observation.In patients with stroke (33) and subarachnoidhemorrhage (34), mannitol enters the CSF invery low concentrations. However, in one exper-imental study mannitol was found in the brainparenchyma after repeated doses, and morewater accumulated in already edematousregions (1), suggesting that mannitol accumu-lation may lead to rebound cerebral edema (seethe following section).

Mechanisms of ICP Reduction

Osmotic agents unequivocally lower ICP. Formannitol, the fall in ICP is influenced by thedose (35), pretreatment ICP (36), and rate of infu-sion (37). A wide range of doses and scheduleshas been reported in the literature. Smaller, morefrequent doses (38) and as-needed use when ICPexceeds a threshold (39) may reduce the totalamount of drug required.

The mechanism by which osmotic agents actto lower ICP is a matter of debate, though. Thereare three leading theories:

• Osmotic agents extract water from the brain

• Osmotic agents raise blood pressure, result-ing in autoregulatory vasoconstriction anda fall in CBV

• Osmotic agents lower serum viscosity, lead-ing to reduced cerebral blood volume (CBV)

Although these theories were developed toexplain the effect of mannitol, the physiologi-cal basis for them applies to HS as well.

Extraction of Brain Water

When administered in clinical doses to nor-mal rabbits (40) and monkeys (41), mannitolreduces brain water by about 2% and concomi-tantly reduces ICP.

The effect of mannitol in brain-injured ani-mals has been quite variable. This may beexplained in part by the differing doses usedand inconsistent correction of mannitol-induceddiuresis among the models. In a hemisphericcold-lesion model of cerebral injury in cats, asingle dose of mannitol produced a fall in watercontent in the unaffected hemisphere but nochange in the hemisphere containing the lesion.Interestingly, the decline in ICP preceded thefall in brain water (42). Using a similar model,however, other investigators reported that adose of mannitol reduced the water content ofthe lesioned but not the normal hemisphere (43).Serial doses of mannitol in a rat model of mid-dle cerebral artery (MCA) stroke led to a reduc-tion in the volume of the normal but not theaffected hemisphere, but only if urine outputwas not replaced (44). In these experiments coad-

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ministration of isotonic fluids to prevent hypo-volemia associated with mannitol led to a dose-dependent reduction in the water content of theinfarcted hemisphere, whereas the water con-tent in the normal hemisphere fell only afterlarge doses of mannitol (45).

Studies of the effects of mannitol in humanshave been surprisingly few. In one study intra-operative biopsies of white matter taken fromtraumatic brain injury (TBI) patients before andafter a single dose of 0.28 g/kg of mannitolshowed a significant decrease in brain watercontent (46). Similarly, in brain tumor, brainwater content fell progressively after adminis-tration of 1–2 g/kg of mannitol (47). In ischemicstroke with midline shift, preferential shrink-age of the noninfarcted hemisphere was found(48). Of note, the effect was considerably blunt-ed in one patient who had received several largedoses of mannitol over the 24 hours before thestudy.

Hypertonic sodium chloride solutions are alsoeffective in lowering ICP and reducing brainwater. After the administration of a 30% sodi-um chloride solution, normal brain shrinks vis-ibly (to the naked eye) (9). Administation of 7.5%saline reduced brain water in a sheep model ofhead injury (49). Equi-osmolar doses of 20%mannitol and 7.5% saline produced similarchanges in ICP in a focal cryogenic injury modelin the rabbit (50). In a model of trauma, whichincluded both a focal head injury and hemor-rhagic hypovolemia, volume resuscitation with6.5% saline lowered brain water in both hemi-spheres (51).

Autoregulatory Vasoconstriction Resultingin Reduced CBVUnder normal resting conditions cerebral

blood flow (CBF) remains stable over a widerange of cerebral perfusion pressures (CPP)through autoregulatory vasodilation and vaso-constriction of penetrating arterioles. It has beenproposed that mannitol lowers ICP as follows:a bolus of mannitol induces movement of waterinto the vascular space, expanding intravascu-lar volume. This causes a rise in blood pressure,which increases CPP, which is followed by

autoregulatory vasoconstriction. According tothis theory the fall in CBV accounts for the fallin ICP. Uncontrolled clinical observations havebeen published to support this theory (52), butcomparative data are lacking (53,54). BecauseHS is also a potent intravascular volumeexpander and raises blood pressure, it shouldbe expected to act in a similar fashion. This the-ory has been challenged on the grounds that (1)mannitol does not lead to a constant rise in bloodpressure and the response is often mild and (2)autoregulation is frequently impaired in cere-bral injuries (55–59).

Reduction in Viscosity Raising CBF andLeading to Cerebral VasoconstrictionBased on the observation that mannitol con-

stricts pial arterioles and venules (60), anotherhypothesis argues that changes in blood vis-cosity explain the effect of mannitol on ICP.According to this theory, the lowering of vis-cosity in response to mannitol causes CBF toincrease. This rise in CBF and therefore oxygendelivery leads to vasoconstriction to return oxy-gen delivery to baseline levels. In one study,blood viscosity fell, independent of the fall inhematocrit, after patients were given mannitol.However, the reduction in viscosity occurredonly if there was red cell deformity (26). BecauseHS solutions shrink red blood cells and increasetheir deformity (27), they might be expected tolower ICP though a similar mechanism (28).

Both the reduced viscosity and the reducedCBV theories have limitations. Attempts toreproduce mannitol-induced vasoconstrictionin pial vessels have been unsuccessful (61). Inaddition, CBV rises after administration of man-nitol to normal rats (62) and dogs (63) and in acat model of brain edema (64). The only studyin humans found that CBV as measured bypositron emission tomography increased with-in minutes of mannitol administration (65).

The effect of mannitol on cerebral metabo-lism is poorly understood. When mannitol isinfused intra-arterially (to open the BBB foradministration of chemotherapy for braintumors), cerebral oxygen consumption rises (66).




Mannitol was found to increase CBF and metab-olism out of proportion to the fall in ICP in amodel of head injury (67). On the other hand,in TBI patients, mannitol lowered ICP andimproved CPP but did not influence jugularvenous or brain tissue oxygen (68). Nothing isknown about the effect of HS on cerebral metab-olism.

Clinical Experience With OsmoticTherapy

Traumatic Brain Injury

Elevated ICP may occur in TBI in the pres-ence of hematomas or cerebral edema andremains a major focus of patient care. Althoughhyperventilation, sedation, and metabolic sup-pression have a role in the management ofintracranial hypertension in TBI, osmotic agentsremain the mainstay of treatment. Until recent-ly, mannitol was the only agent routinely usedfor this purpose in the United States.

Several studies clearly demonstrate that man-nitol can lower elevated ICP in TBI patients(3,39,69–72). Hypertonic saline has also beenshown to lower ICP in this population (6), whilesimultaneously expanding intravascular vol-ume by drawing in intracellular water(49,73–77). Thus, HS may correct two problemsin TBI patients: cerebral edema resulting fromhead injury and hypovolemia resulting fromblood loss. In the only prospective randomizedcontrolled trial of osmotic therapy in TBI, HSwas superior to lactated Ringer’s solution inreducing elevated ICP. However, the impact onoutcome was not studied (25).

Cerebral Infarction Infarction of the entire territory of the MCA

occurs in 10–20% of patients with ischemicstroke (78–80). Patients with these or other largehemispheric infarctions (LHI) have a high riskof neurological deterioration resulting fromcerebral edema (2,81) . Edema followingischemic stroke begins during days 1–3, peaksduring days 3–5, and subsides by 2 weeks(82–84).

Treatment strategies for managing patientswith LHI have replicated the interventions usedin TBI. There have been few investigations ofthese therapies in patients with ischemic strokeand no uniform approach to their use. Despitethis, osmotic therapy is often viewed as inef-fective in LHI (85), leading some to argue forthe use of more invasive treatments such as hem-icraniectomy and hypothermia (85–88).

In some (89), but not all (90), experimentalmodels of stroke, administration of mannitolreduces infarct size, decreases edema, andreduces neurological deficit (44,91–93).However, there are remarkably few studies onthe use of mannitol in stroke patients. Two ret-rospective reviews found that mannitol was noteffective in improving neurological condition(94,95). Mannitol transiently reduced elevatedICP in another study of stroke patients, but itsimpact on outcome was not determined (96). Ina recent observational study, mannitol use didnot result in improved outcome at 30 days or 1year (97), and in a prospective controlled trialof 77 patients with large strokes, was not asso-ciated with any benefit or harm (95). Yet, evenwith this lack of convincing evidence of effica-cy, the American Heart Association guidelines(98) and others recommend the use of mannitolto treat poststroke edema.

There are even fewer studies of the use of HSfor the treatment of post-stroke edema. Animaldata suggest it may be harmful, with HS increas-ing brain water and infarct volume in one ratmodel (99,100). Data in human ischemic stroke,however, are more encouraging. HS has beenreported to effectively treat “mannitol-resist-ant” intracranial hypertension after stroke(101,102), but its impact on outcome is unknown.

Mannitol Versus Hypertonic Saline

Several studies have compared the use of HSwith mannitol in patients with acute brain injury.Although the two treatments appear to havesimilar efficacy in lowering ICP, it is difficult todraw any definite conclusions because the stud-ies involved a wide range of sodium concen-trations, osmotically equivalent doses of the two

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agents were rarely used, and HS was oftenreserved for patients with intracranial hyper-tension “refractory” to mannitol.

Comparative data in stroke are scarce. A fewsmall studies suggest that both treatments effec-tively lower elevated ICP (96,103) but these stud-ies suffer from the same limitations discussedpreviously. None have addressed the prophy-lactic use of osmotic agents to treat swelling andtissue shifts before the onset of intracranialhypertension. This question of timing is criticalin ischemic stroke patients because clinical her-niation frequently occurs before ICPbecome ele-vated (2,104,105).

Potential Complications of Mannitol

“Rebound” Intracranial HypertensionOften cited as a major limitation to the use of

mannitol, “rebound” intracranial hypertensionis alleged to occur as the drug penetrates thebrain (especially in regions with a disruptedBBB) and accumulates to such a degree that itdraws water back into the brain (106). Becauseurea penetrates the brain much more easily thanmannitol (13,106), the early reports of reboundICP elevation with urea may be explained bythis hypothesis. Whether mannitol accumulatesin the brain and whether rebound intracranialhypertension occurs after its use are unclear,however.

Mannitol administered in a single intra-venous dose to normal subjects enters the CSF,but peak CSF concentrations never exceed peakplasma concentrations (32). In a cold-lesionmodel, multiple doses (but not a single dose)led to accumulation of labeled mannitol in ede-matous white matter that exceeded plasma con-centrations and that was associated with a 3%increase in brain water of edematous regionsbut no change in other brain regions (1). Theclinical relevance of this observation is uncer-tain. In an elegant study magnetic resonancespectroscopy was used to detect mannitol with-in the brain of a patient who had received man-nitol despite being in renal failure (107). Theinvestigators were able to detect the presence ofmannitol within damaged areas of brain after

administration but before dialysis. After dialy-sis the mannitol was not longer present. Thissuggests that, although mannitol may enter thebrain by diffusing down its concentration gra-dient, as it is cleared from the blood, mannitolleaves the brain.

There are numerous reports of mannitol-asso-ciated ICP elevation attributed to reboundintracranial hypertension (108). Although man-nitol removes water less effectively from injuredthan noninjured brain, it is not clear whether thiscan result in a rebound increase in ICP. An alter-native explanation for the increase in ICP is thatthe administration of relatively hypotonic fluidsto hyperosmolar patients combined with a risein the number of intracellular osmotic particles(the brain’s adaptive response to hyperosmolarstates described previously) induces movementof water back into regions with disrupted BBBand increased water permeability (65).

Increase in Tissue ShiftsIf, as suggested by some experimental data,

administration of mannitol reduces the watercontent of normal but not damaged brain, andif it accumulates in damaged brain tissue whereit potentially worsens cerebral edema, then itmight follow that mannitol use in large cerebralinfarctions may actually cause neurologicaldeterioration by preferentially shrinking non-infarcted tissue and aggravating midline tissueshifts (2). To address this concern, we studiedthe effect of a single large dose of mannitol onmidline shift and hemispheric volume inpatients with large hemispheric infarction.

Effect of Mannitol on Midline Shift in PatientsWith Large Hemispheric InfarctionSix patients with complete MCA infarction,

neurological deterioration, and CT evidence of13 ± 2 mm midline shift were studied. T1-weight-ed, three-dimensional multiplanar rapid acqui-sition gradient echo image data sets acquired at5- to10-minute intervals before and immediate-ly after a 1.5 g/kg bolus of mannitol. Mannitoladministration had no significant effect on hor-izontal or vertical midline shift. Mean GlasgowComa Scale scores and Middle Cerebral Artery




Stroke Scale scores for the group did not change,but the Middle Cerebral Artery Stroke Scalescore improved by 15 points in two patients, theGlasgow Coma Scale score improved by 1 pointin three patients, and pupillary light reactivityreturned in two patients. No patient worsenedafter administration of mannitol (109).

Effect of Mannitol on Hemispheric Volumein Patients With Large Hemispheric Infarction

We subsequently used the more sensitivebrain boundary shift integral method to deter-mine if mannitol reduces brain volume inpatients with large hemispheric infarction (Fig.1). We measured changes in brain volume with-in a thin region of interest comprising thebrain/CSF boundaries of the entire brain (48)before and approximately 30 minutes after com-pletion of the mannitol infusion in the samepatients described previously and in normalcontrol subjects who did not receive mannitol.

Relative to baseline, total brain volumedecreased by 8.1 ± 2.8 cc (0.6%, p < 0.0001) aftermannitol infusion in the patients (Fig. 2) com-

pared with no change in brain volume amongcontrol subjects. Of note, in all patients, the non-infarcted hemisphere shrank more (0.8 ± 0.4%)than the infarcted hemisphere (0.0 ± 0.5%, p<0.02), suggesting that mannitol preferentiallyentered the infarcted hemisphere.

Osmolality data were available for fourpatients in whom mean baseline brain volumewas 1358 mL and serum osmolality increasedfrom 299 to 306 mOsm/L. The measureddecrease in brain volume was 8.8 mL comparedwith a predicted volume change of 23 mLbecause of movement of water alone.

These data are preliminary and must be inter-preted with caution. They suggest that, over thefirst hour after mannitol administration, mid-line shift does not change, the normal hemi-sphere shrinks, and the infarcted hemispheredoes not change. What happens to the volumeof the infarcted hemisphere after the first houris not known, but it seems reasonable to expectthat as mannitol diffuses out of this tissue, it willshrink as well. Taken together these results donot demonstrate any harmful anatomic effects

Osmotic Therapy ____________________________________________________________________________225


Fig. 1. Brain boundary shift integral in a normal control subject.The region of interest (ROI) covers all bound-aries between brain and cerebrospinal fluid (CSF). Illustrated is a highly magnified portion of the brain edge show-ing the ROI. A single box represents each voxel and the intensity represents the average signal strength frombrain and CSF.Voxels containing both brain and CSF will have intermediate intensities.When brain shrinks awayfrom the inner table of the skull, the intermediate voxels contain proportionally less signal from brain, so thevoxel intensity decreases.Therefore, the average intensity of the entire ROI will decrease.


of mannitol. This, coupled with the hint of clin-ical improvement, argues for continued use ofmannitol in this setting.

Monitoring Mannitol UseThe potential complications of mannitol accu-

mulating in damaged brain tissue and worsen-ing tissue shifts appear to be more of an issue ifthe drug is not completely cleared from the bloodbetween administrations. Because hospital lab-oratories are not equipped to measure manni-tol levels, it is unfortunately not possible tomonitor mannitol clearance from the blood rou-tinely. The osmolal gap (OG), which can be deter-mined using electrolytes routinely measured inhospital laboratories, might be a useful surro-gate for mannitol levels.

Osmolality (measured directly as mOsm/kg)represents the concentration of solutes dissolvedin a solvent as opposed to the volume of the sol-vent, which is expressed as osmolarity (calcu-lated from electrolytes as mOsm/L). Because

the solvent in plasma is water and 1 L of waterweighs 1 kg, the terms osmolality and osmo-larity are almost interchangeable when talkingabout body fluids. The OG is the differencebetween osmolality and osmolarity and is mostcommonly used to detect the presence of unmea-sured osmoles such as mannitol. Therefore, aslong as other unmeasured osmoles are not pres-ent, the OG could be useful as an indirect reflec-tion of mannitol serum levels.

Although valuable in monitoring for toxici-ty associated with repeated dosing of mannitol,osmolality is not very useful in predicting serummannitol levels (2). This is because osmolalityreflects concentrations of both measured andunmeasured osmoles. Thus, a high serum osmo-lality would be seen in the setting of hyperna-tremia (measured osmole) and in the case ofincompletely cleared mannitol (unmeasuredosmole), for example.

We postulated that the osmotic gap wouldcorrelate with serum mannitol levels (110).Using blood samples collected from 96 healthymedical students, 8 neurology/neurosurgeryintensive care unit (NNICU) patients not receiv-ing mannitol, and 10 NNICU patients receivingmannitol, we determined osmolality using thefreezing point depression method and calcu-lated osmolarity from routinely performed elec-trolyte measurements. In patients receivingmannitol, OG was calculated using six differentformulas from blood samples drawn immedi-ately before and 10 minutes and 1 hour after adose of mannitol. The mean OG did not differbetween healthy subjects, ICU patients notreceiving mannitol, and before a mannitol dosein ICU patients receiving mannitol. Osmolalityincreased at 10 minutes after mannitol admin-istration, however, and began to decline at 1hour.

Osmolal gap correlated well with mannitollevels. Calculation of OG using the formula 1.86(Na K) (blood urea nitrogen/2.8) (glucose/18)+ 10 provided the best correlation (r = 0.80) (Fig.3), achieving an OG:mannitol ratio of 1.0:0.81.Thus OG may be useful in monitoring clearanceof mannitol between bolus administrations.



Fig.2. Change in brain volume relative to baseline scanfor six patients with large hemispheric infarctions given1.5 g/kg mannitol.Open squares represent patient whoreceived multiple doses of mannitol before the study.Dark bar on axis indicates the approximate durationof infusion (48).


The 320-mOsm CeilingThat mannitol should be withheld if the serum

osmolality exceeds 320 mOsm is a commonlyheld belief, but the origin of this threshold isobscure. In the evidenced-based guidelines forthe management of severe head injury devel-oped by the Brain Trauma Foundation, the state-ment, “Serum osmolarity should be kept below320 mOsm when there is concern for renal fail-ure” (111) is supported only by an abstractinvolving a small number of patients treatedwith extremely high-dose (0.25 – 0.5 g/kg/hour)continuous infusions of mannitol. No patient inthis report developed renal failure with an osmo-lality below 400 mOsm (112). (The second ref-erence cited [113] does not directly discuss theissue.) In our center the 320 mOsm threshold isroutinely crossed without inducing renal fail-ure. Close attention to fluid replacement to coun-teract the potent diuretic effect of mannitol andavoidance of frequent, large intermittent dosesor continuous infusions that may result inincomplete excretion of the drug appear to bekey to preventing renal failure.

A second concern is that osmolality exceed-ing 320 mOsm will exacerbate cerebral injury.Although dramatic and rapid raising of osmo-

lality resulted in rebound cerebral edema in anexperimental model, the relevance of theseobservations to the clinical arena where osmo-lality is raised much more slowly is unknown.

To investigate the effect of elevated osmolal-ity on outcome, we performed a retrospectiveanalysis of 605 consecutive adult patients treat-ed with mannitol (114). Hypernatremia (>145mEq/L) occurred in 147 patients (24%) and wasmild (151–155 mEq/L) in 35%, moderate(156–160 mEq/L) in 27%, and severe (>160mEq/L) in 38% of patients. Mortality increasedwith increasing hypernatremia, but, only severehypernatremia was independently associatedwith increased mortality (odds ratio 4.77; 95%confidence interval 2.37–9.58). Therefore, risingserum sodium (and thus osmolality) was notassociated with worse outcome until sodiumconcentration exceeded 160 mEq/L, whichwould be equivalent to an osmolality of approx-imately 335–340 mOSm in a patient with nor-mal glucose and blood urea nitrogen levels.

Clinical Use of Hypertonic SalineThe literature provides little guidance regard-

ing concentration, dose, timing, and goals forthe clinical use of HS. Because of a more exten-sive experience with mannitol, lack of data sug-gestive of an advantage of HS over mannitol,and additional potentially beneficial physio-logical effects of mannitol, we reserve HS forsecond-line therapy in patients with unsatis-factory control of ICP or tissue shifts who havea climbing osmotic gap or rise in serum creati-nine (in the absence of hypovolemia). In this set-ting, 23.4% saline and mannitol are given inequi-osmolar doses based on the mannitol dos-ing being given at that time. When serum sodi-um concentration is approaching 160 mEq/L,doses are usually reduced.

ConclusionsThe use of osmotic agents is routinely rec-

ommended in the management of cerebraledema associated with TBI and cerebral infarc-tion despite a lack of evidence of beneficial effecton outcome.

Osmotic Therapy ____________________________________________________________________________227


Fig. 3. Correlation between osmotic gap and manni-tol levels.


These agents appear to exert their effect pri-marily by drawing water out of the intracellu-lar and interstitial spaces, resulting in temporarybrain shrinkage. In addition to the osmoticeffects, these agents produce hemodynamiceffects that necessitate close monitoring of car-diac and fluid status. Mannitol and hypertonicsaline appear to be equally effective at reducingICP in brain-injured patients, but comparativedata are extremely limited.

A single experimental model suggested that,when given in multiple doses, mannitol mayaccumulate in injured brain. Yet, mannitol wasshown to leave the brain as it was cleared fromthe blood in a patient studied with chemical shiftimaging. Whether mannitol accumulate in otherclinical settings remains unanswered. However,it seems unlikely that this could account forrebound edema because mannitol is not meta-bolically trapped in the brain and there is noreason not to expect that it would exit the wayit entered, down its concentration gradient.

Some experimental data also suggest thatmannitol preferentially reduces the water con-tent of normal brain, leading to the potential foraggravation of midline tissue shifts. Althoughpreferential shrinkage of the noninfarcted hemi-sphere probably does occur with mannitoladministration in patients with large hemi-spheric stroke, the differential in volume changebetween hemispheres is insufficient to cause ameasurable change in midline shift.

Monitoring for toxicity associated with man-nitol use typically relies on measurement ofosmolality, but osmolality is not predictive ofmannitol levels. On the other hand, calculationof the osmolal gap (the difference between osmo-lality and osmolarity) correlates well with man-nitol levels and may be useful in monitoringclearance of mannitol between bolus adminis-trations and limiting cerebral and renal toxicity.

The dogma that mannitol should be withheldif the serum osmolality exceeds 320 mOsmbecause of the risk of renal failure and worsen-ing of cerebral edema has not been substantiat-ed. Careful monitoring of fluid balance andcontrolled raising of osmolality to avoid incom-

plete drug excretion may allow for this thresh-old to be crossed safely.

Fact or Fiction?• Mannitol accumulates in injured brain—

probably fiction• Mannitol shrinks only normal brain—prob-

ably fact• Mannitol increases midline shift—fiction• Osmolality can be used to monitor mannitol

administration—fiction• Mannitol should be not be administered if

osmolality is > 320 mOsm—fiction• Hypertonic saline is equally effective as man-

nitol—unknown

AcknowledgmentThis work was supported by grants from the

National Institutes of Health (NS35966 and1K23NS044885).

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