(Stroke. 1997;28:1437-1444.)
© 1997 American Heart Association, Inc.
Articles |
Multiple-Dose Mannitol Reduces Brain Water Content in a Rat Model of Cortical Infarction
From the Department of Neurology and Center for the Study of Nervous System Injury, Washington University Medical Center, St Louis, Mo.
Correspondence to Chung Y. Hsu, MD, PhD, Department of Neurology, Washington University, Box 8111, 660 S Euclid Ave, St Louis, MO 63110.
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Background and Purpose Repeated use of mannitol in the setting of ischemic infarction is a controversial and poorly defined therapeutic intervention. The purpose of this study was to examine the effects of repeated mannitol infusions on brain water content and tissue pressure in a well-defined rat model of focal ischemic stroke.
Methods Mannitol infusions (0.5, 1.5, or 2.5 g/kg) were given by intravenous bolus 4 or 24 hours after 90-minute transient cortical ischemia in the territory of the right middle cerebral artery in rats and every 4 hours thereafter for a total of 24 hours. Fluid replacement was limited to 0.5 mL IV isotonic saline administered immediately after each mannitol dose. Control rats received 0.5 mL IV saline at the same intervals and were otherwise under ad libitum conditions. Water contents (percent H2O) of whole hemispheres and of cortical biopsies were measured with the wet-dry method, and blood samples were analyzed for plasma osmolality and chemistries. In a subgroup of rats, tissue pressure was also measured within the hemisphere ipsilateral to the infarct.
Results Repeated mannitol infusions resulted in a dose-dependent increase in plasma osmolality and a dose-dependent decrease in the percent H2O of the ischemic middle cerebral artery cortex and ipsilateral hemisphere. In contrast, percent H2O of the contralateral cortex and hemisphere was significantly decreased only in the groups given the highest dose of mannitol (2.5 g/kg). Mannitol infusions at a dose of 1.5 g/kg begun 24 hours after reperfusion were also associated with a significant reduction of tissue pressure.
Conclusions In a rat model of ischemic cortical infarction, repeated mannitol infusions resulted primarily in a decrease in the percent H2O of the infarct and ipsilateral hemisphere, as well as decreased tissue pressure.
Key Words: brain edema • cerebral infarction • mannitol • osmosis • rats
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Introduction |
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Edema formation leading to brain swelling accounts for the majority of fatalities that occur during the first 2 weeks after large hemispheric stroke.1 2 Secondary injury to the brain stem and diencephalic structures associated with interhemispheric shift may also contribute to depressed level of consciousness in persons with massive cerebral infarction.3 The fluid management of these stroke patients is controversial. Although there are no therapeutic interventions of proven value in ameliorating ischemic edema and brain swelling, one of the options in intensive medical care has been to offer "osmotic therapy"4 5 with compounds such as mannitol. Dosing of mannitol by intravenous bolus is a highly effective, time-tested means of rapidly lowering intracranial pressure or improving cerebral compliance in a number of acute neurological disorders and perioperative settings.5 6 7 However, there is relatively little information available regarding the net impact of repeated administration of mannitol on the water content, and hence volume, of damaged brain tissue, particularly when the BBB is defective. This issue is clinically important because physicians are frequently faced with the medical management of a protracted course of brain swelling that may follow cerebral ischemia.
Several experimental studies have suggested that acute administration of hypertonic solutions may reduce the water content and volume of normal, but not of damaged, brain tissue.5 8 9 10 This discrepancy is most often explained by referring to the necessity of an intact (ie, relatively impermeable) BBB for osmotic agents to establish sufficient osmotic gradients to achieve their tissue-shrinking effects.8 9 10 Therefore, the argument has been posed that sustained mannitol infusions may actually aggravate interhemispheric movement of tissue or "midline shift" owing to the selective reduction in volume of undamaged tissue contralateral to a focal lesion.11 Furthermore, appropriate concern has been raised that a nonmetabolized compound such as mannitol may penetrate the more permeable vessels of damaged tissue, accumulate, and result in iatrogenic worsening of edema secondary to its osmotic activity.10 12
A "rebound" increase in intracranial pressure attributed to accumulation of exogenous osmoles in brain parenchyma or CSF has been recurrently implied,10 12 13 14 although never definitively characterized.15 16
Despite these concerns, the effects of mannitol infusions on brain edema in the setting of ischemic infarction remain largely unknown. Because osmotic agents exert complex effects on both intracranial volume dynamics and the systemic circulation,17 18 19 the net impact of repeated mannitol infusions on the damaged brain is likely to reflect multiple, possibly countervailing influences. The results from experiments involving very large, acutely developing osmotic gradients in laboratory animals may not be directly relevant to clinical therapeutics. It is unclear what net effect gradual hyperosmolar dehydration (more typical of clinical circumstances) would have on the intracranial distribution of water when the edematous lesion is considered as part of a system of dynamically exchangeable compartments of fluid. In light of these questions, the present study was undertaken to investigate the impact of a multiple-dose regimen of bolus mannitol on infarct-associated water content and tissue pressure. To this end, a well-established rat model of focal cortical ischemic injury associated with a consistent pattern of BBB damage and edema formation was used.20 21 22 23
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Materials and Methods |
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Protocols
Mannitol was given intravenously to different groups of rats with cortical infarction in the territory of the right MCA (see below for specific methods) according to the following protocols (Fig 1
): (1) In the 4-hour delay mannitol group (n=32),
beginning 4 hours after 90-minute transient ischemia and every
4 hours thereafter, a total of five intravenous bolus doses
of mannitol were given over a 24-hour period. This group was further
divided into three subgroups, each receiving mannitol doses of 0.5
(n=7), 1.5 (n=6), or 2.5 (n=9) g/kg body wt, respectively. A 0.5-mL IV
bolus of isotonic saline was injected after each mannitol infusion.
Mannitol-treated rats had free access to food but were otherwise denied
access to drinking water or other fluids during the entire experimental
period. Rats with identically produced right MCA infarctions served as
controls (n=10). Control animals also received indwelling
intravenous catheters and 0.5-mL IV boluses of isotonic
saline every 4 hours after ischemia, but there was no attempt
to match the total amount of fluid infused into mannitol-treated rats.
Control rats were otherwise under ad libitum conditions (ie, they had
free access to food and water). All rats were killed 24 hours after
ischemia for tissue and plasma analyses. (2) In the
24-hour delay mannitol group (n=27), beginning 24 hours after 90-minute
ischemia/reperfusion and every 5 hours thereafter, a total of
five bolus doses of intravenous mannitol were delivered at
0.5 (n=7), 1.5 (n=8), or 2.5 (n=5) g/kg body wt, as described above.
Concurrent controls (n=7) with identically produced right MCA
infarctions received 0.5-mL IV boluses of saline every 4 hours but were
otherwise under ad libitum conditions during the experimental period.
All rats were killed 48 hours after ischemia for tissue and
plasma analyses. In one of the subgroups (1.5 g/kg mannitol,
n=6), tissue pressure was measured under chloral hydrate sedation over
a 30-minute period immediately before the rats were killed, and values
were compared with those obtained from controls (n=7).
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Focal Ischemic Infarction Model in the Rat
Adult, male Long-Evans rats weighing 320 to 412 g were used
in these studies (n=59).
All procedures were approved by the Washington University Animal Care Committee and were consistent with the National Institutes of Health guidelines for small animal experimentation. Severe focal ischemia of the right MCA territory was produced with the use of microsurgical techniques, as discussed in detail in previous publications.20 22 Briefly, after administration of general anesthesia with pentobarbital (45 mg/kg body wt IP), the CCAs were exposed and isolated. A 2-mm burr hole was then made at the junction of the zygomatic arch and squamous bone with a dental drill. The right MCA trunk just distal to the rhinal fissure was identified and ligated with 10-0 microsuture (Ethicon), and interruption of blood flow was confirmed under the dissecting microscope (Bausch & Lomb). The CCAs were then occluded by applying atraumatic aneurysm clips 2 to 3 mm below the carotid bifurcation. After 90 minutes of ischemia the MCA ligature and CCA clips were removed, and reperfusion was documented with the dissecting microscope. With pentobarbital anesthesia, blood pressure and arterial blood gasses were maintained within the normal range, and temperature stability (37±0.5 C) was ensured with the use of a thermo-controlled heating pad. After recovery from anesthesia (return of righting reflexes), the animals were randomly assigned to either control or one of the mannitol-treated subgroups and observed for 24 to 48 hours.
Bolus Administration of Mannitol
A 25% solution of mannitol (250 mg/mL, 1372 mOsm/L; Abbott
Laboratories) was delivered through an indwelling polyurethane femoral
venous catheter fitted with a heparin lock that was tunneled
subcutaneously to emerge in the interscapular region. Animals were
temporarily immobilized by placement in a cylindrical
plastic housing, and mannitol was infused at the various doses through
a Sage microinfusion pump at 0.5 to 0.75 mL/min. The same concentration
of mannitol solution was used throughout the study, and therefore the
absolute volume of fluid infused in each rat depended on dose (0.5,
1.5, or 2.5 g/kg) and body weight. Preliminary experiments with this
approach demonstrated that bolus mannitol can be given in the dose
range of 0.25 to 2.5 g/kg total body wt to ambulatory animals without
acute morbidity or mortality.
Physiological Parameters and
Quantitation of Brain Edema
All animals were killed 4 hours after the last of five infusions
to maintain a consistent temporal relationship between mannitol
bolus dosing and the measurement of brain tissue water. At the time of
its death, the animal was weighed for comparison with initial
(presurgical) body weight, and a sample of blood was processed for
determination of plasma osmolality. In the 4-hour delay mannitol group,
plasma electrolytes, BUN, and glucose values were also determined so
that osmolality could be calculated and compared with the value
measured by freezing-point depression osmometry. To discern
hemodynamic changes caused by mannitol treatment, a
femoral arterial catheter was placed with the animal under
pentobarbital anesthesia (0.05 mg/g body wt IP) in a
representative number of animals in each group (n=17
and n=16 in the 4- and 24-hour delay groups, respectively) immediately
before the animal was killed with the use of a Micro-Med transducing
system.
Brain water was quantitated by the wet-dry weight method as described previously.22 Briefly, animals were killed at the end of the experiment by decapitation under deep pentobarbital anesthesia, the brain was removed, and the cerebral convexities were exposed in a humidified chamber. Brain tissue samples from the center of the right and left MCA territories were rapidly removed with a cylindrical biopsy tool, and the cortex was separated from subcortical structures. The rhinal fissure was used as an anatomic reference point that defined the lower border of each biopsy. At the time of removal, the medial surfaces of all samples were gently blotted with tissue paper to remove small quantities of adsorbent CSF. Both left and right cortical samples and the remaining tissues of both hemispheres were then separately weighed with a basic precision scale (Saltorius 2462, Saltorius Werke) to within 0.1 mg and dried to constant weight in a vacuum oven (Precision Scientific) at 80 C and low vacuum. The percent H2O of each tissue sample was then calculated according to the following equation: % H2O=Wet Weight-Dry Weight/Wet Weightx100.22
Measurement of Plasma Osmolality and Electrolytes
The osmolality of plasma (milliosmoles per liter) was measured
from samples obtained from fresh arterial blood with an
automated freezing-point depression micro-osmometer (Advanced
Instruments). This value can be determined with an accuracy of ±2
mOsm/L with this instrument. In most animals in the 4-hour delay group
(n=23), plasma concentrations of sodium, BUN, and glucose were
determined by standard ion-sensitive electrode and enzymatic methods
through the Washington University clinical laboratories, so that the
contribution of major components of plasma osmolality could be
separately calculated. A significant "osmolar gap" was defined as
any difference greater than 10 mOsm/L between the measured osmolality
of plasma and the calculated plasma osmolality, the latter derived from
the following formula: 2 (Na)+(Glucose/18)+(BUN/2.3).24 In
this setting, a significant osmolar gap was interpreted as an
accumulation of mannitol within the plasma between doses.
Measurement of Tissue Pressure
In a subgroup of rats in the 24-hour delay mannitol group (n=6)
and concurrent controls (n=7), tissue pressure was recorded with an
implantable pressure microtransducer system (Micro-Med). Rats were
sedated with chloral hydrate (250 mg/kg IP) and the head fixed in a
stereotaxic frame. Chloral hydrate was used rather than
pentobarbital at this phase of the study because the latter compound
may potentially significantly influence intracranial pressure. After
supplementary local anesthesia, the parietal scalp was
incised and reflected laterally, and a 2-mm burr hole was made with a
dental drill at the same coordinates in all animals: 3 mm
posterior and 3 mm lateral to the bregma over the right cerebral
convexity. The dura mater was then carefully punctured with a 16-gauge
needle, and a saline-filled polyurethane catheter (PE-50) with a
perforated tip was stereotaxically lowered to a depth of
4 mm with respect to the outer table of the skull. The tip of the
catheter came to rest within the depths of the cortical infarct; this
position had been confirmed by gross histological
analyses in preliminary experiments. The margins of the
craniostomy were then tightly sealed with methyl methacrylate epoxy,
and the catheter was fixed firmly to the skull. Pressure transduction
from the low-compliance, saline-filled catheter was achieved with a
low-pressure microtransducer coupled to a digital monitor (Micro-Med).
Before each pressure-recording session, the transducer was
zeroed with respect to the height of the interaural line in each
subject, a position that remained constant throughout each experiment.
Correct placement and appropriate transduction were assessed in each
rat by observing the expected transient 15 to 25 mm Hg increase
of brain tissue pressure in response to anterolateral cervical
compression (Queckenstadt maneuver). Data from subjects without an
appropriate response to cervical compression were discarded (n=1). In
each pressure recording session, 30 minutes was allowed for
achievement of steady state conditions after placement and zeroing of
the microtransducer. Output from the microtransducer was set to read
out an average pressure reading from the succeeding 5 minutes every 5
minutes. Subsequently, the tissue pressure was recorded over a
30-minute period, and averaged values were calculated for each
subject.
Statistical Analysis
Statistical analysis was performed between control and
mannitol-treated subgroups. Differences between measured
parameters (percent change in total body weight, measured
plasma osmolality, calculated plasma osmolality, osmolar gap, mean
arterial blood pressure, total brain weight, percent
H2O of ipsilateral and contralateral hemispheres, and
percent H2O of infarct core and contralateral homotopic
cortex) were tested for significance with ANOVA. The significance level
between groups was assessed with a post hoc t test. In the
case of tissue pressure measurements (one test and one control
subgroup) or comparisons between two mannitol-treated subgroups,
significance was tested directly with Student's t test. A
value of P<.05 was considered statistically significant.
All values in the Table are given as mean±SD.
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Physiological Parameters
As shown in the Table
, reduction in total body
weight was observed in all animals over the course of 24 hours. In the
control subgroups, weight loss was modest and ranged from a mean of
3.9±0.75% to 6.6±0.84% in the 24- and 4-hour delay groups,
respectively. In contrast, in the high-dose mannitol subgroups, weight
loss was severe and ranged from 14.6±2.8% to 15.8±3.1% in the 24-
and 4-hour delay groups, respectively. The lower-dose mannitol regimens
were associated with intermediate degrees of weight loss. Brain weights
were also reduced in proportion to the degree of total body weight
loss. Repeated mannitol infusions produced a dose-dependent increase in both the measured and calculated plasma osmolalities. The rise in calculated plasma osmolality in the 4-hour delay group paralleled an increase in sodium and BUN concentrations (data not shown). An osmolar gap was detected in the 4-hour delay subgroups receiving 1.5-and 2.5-g/kg mannitol infusions, most likely indicating increases in the concentration of mannitol within the plasma. Calculated plasma osmolality and osmolar gaps were not determined in the 24-hour delay group, since general trends had been established. In the 4-hour delay group, mean arterial blood pressure was significantly reduced in the high-dose (2.5 g/kg) mannitol subgroup at the end of the experimental period. There were no significant changes in terminal blood pressure in the 24-hour delay group at any mannitol dose.
Impact of Mannitol on Brain Water Content
Fig 2 depicts a dose-dependent reduction in tissue
water content in the hemisphere ipsilateral to the infarction. Compared
with these values in control animals, statistically significant
reductions in percent H2O in the ipsilateral hemisphere
were observed in all subgroups receiving repeated mannitol infusions in
both the 4- and 24-hour delay mannitol groups. The greatest decreases
in percent H2O in the ipsilateral hemisphere occurred in
animals receiving 2.5-g/kg boluses. In contrast, the percent
H2O in the contralateral hemisphere was reduced
significantly only in the 2.5-g/kg subgroup in both the 4- and 24-hour
delay groups (Table).
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Although there is a clear trend indicating a dose-dependent effect of
the multiple-dose mannitol regimens on the percent H2O in
the ipsilateral hemisphere, the mean difference in percent
H2O in the ipsilateral hemisphere between control rats and
those given the 0.5-g/kg dose of mannitol (1.025%; data combined from
both 4- and 24-hour delay groups) represents 62% of the mean
difference resulting from the much larger dose of 2.5 g/kg (1.72%;
data combined from both 4- and 24-hour delay groups). Therefore,
repeated administration of even the smaller dose of mannitol,
associated with less severe weight loss and less marked
hyperosmolality, resulted in substantial reduction in the percent
H2O in the ipsilateral hemisphere compared with controls.
Furthermore, the mean difference in percent H2O between the
ipsilateral and contralateral hemispheres in individual rats (an index
of interhemispheric volume asymmetry) was actually less in the
subgroups receiving 0.5 g/kg (2.08±0.46%; data combined from both 4-
and 24-hour delay groups) than in those receiving 2.5 g/kg mannitol
(2.49±0.81%; data combined from both 4- and 24-hour delay groups),
although this comparison did not reach statistical significance
(P=.15). Similar trends were observed when the percent
H2O of cortical biopsies was analyzed. Fig 3 depicts a dose-dependent reduction in the percent
H2O of the infarct core in both the 4- and 24-hour delay
mannitol groups. The percent H2O of the contralateral
homotopic cortex was significantly reduced only in the 2.5-g/kg
mannitol subgroups.
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Tissue Pressure
Fig 4 depicts the reduction in tissue pressure
after repeated mannitol infusions in the 24-hour delay, 1.5-g/kg
mannitol subgroup in comparison with concurrent controls. All but one
animal in the control group exhibited an appropriate initial response
to the Queckenstadt maneuver, and data from this subject were
discarded. Mean tissue pressure was reduced from 15.46±3.74 to
8.28±2.4 mm Hg, a difference of 46% (P=.0027). These
values were measured approximately 4 hours after the final bolus dose
of mannitol in the multiple-dose regimen and therefore reflect only the
net result of the intervention on tissue pressure at a single point in
time.
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Discussion |
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Mannitol administration is one of the mainstays of medical management of space-occupying intracranial pathology. It can effectively reduce intracranial pressure or enhance surgical exposure in the acute setting.4 5 6 7 However, despite widespread clinical use and an extensive experimental literature, few studies have documented a clear relationship between repeated mannitol infusions and the water content of the brain in cases of lateralized neuropathology such as ischemic infarction.8 9 12 16 Accumulated evidence from experimental and clinical studies indicates that mannitol infusions and other forms of osmotic therapy exert complex effects on the components of intracranial volume. These may include changes in cerebral blood volume,17 18 25 altered production of CSF, or altered rates of CSF reabsorption.9 19 26 However, the data presented in this and other studies support the view that infusion of hypertonic solutions can cause a reduction in the water content of brain parenchyma, albeit of modest degree.8 27 28 29 30 The water content changes measured in this study are not readily explained on the basis of reduction in the intracranial CSF pool or of cerebral blood volume, although changes in these components (which were not measured separately) may have also occurred. First, given the method of brain dissection used, CSF was virtually excluded from the determination of wet weight and therefore does not contribute materially to the calculation of percent H2O in this study. Second, because the water content of blood is only marginally higher than that of brain parenchyma,31 even a theoretical decrease in cerebral blood volume by 100% as a result of mannitol infusions would not account for the magnitude of reduction in percent H2O of whole brain tissue samples measured with the wet-dry technique.
The main finding of this study is that when systemic dehydration was permitted, repeated mannitol infusions reduced the water content of edematous brain tissue. Notably, water content was significantly reduced in the infarct core after mannitol infusions, a region known to have a damaged BBB in this stroke model.23 The reduction in the water content of the infarct core was comparable whether the beginning of repeated mannitol infusions was delayed 4 or 24 hours after ischemia. The reduction in water content of both the infarcted cortex and ipsilateral hemisphere was roughly dose dependent. In contrast, a statistically significant reduction in the water content of ostensibly normal brain contralateral to the infarct was observed only after repeated infusions of 2.5 g/kg mannitol, the highest dose used in this study. This high-dose regimen was associated with a severe hyperosmolar state and the development of an osmolar gap, the latter most likely indicating accumulation of mannitol within the plasma. It is postulated that significant reduction in the percent H2O of intact contralateral brain tissue was seen only when a sustained osmotic gradient between plasma and parenchyma had developed after the high-dose mannitol infusions, consistent with many previous experimental studies involving hypertonic solutions.8 9 With respect to the issue of interhemispheric or midline shift of brain tissue, it is of interest that while the water content of the ipsilateral hemisphere was significantly decreased after every mannitol regimen used (in comparison with the ipsilateral hemisphere of control animals), the mean difference in water content between ipsilateral and contralateral hemispheres in individual rats (an index of left-right volume asymmetry) was actually lower after infusions of 0.5 g/kg mannitol than the much higher dose of 2.5 g/kg. This paradoxical relationship is most likely explained by the fact that while higher doses of mannitol resulted in a greater absolute decrease in the water content of edematous brain tissue, the higher doses also produced, on average, a proportionately greater decrease in the percent H2O of the contralateral hemisphere. Although midline shift was not measured directly in this study by conventional criteria,3 these data suggest that more severe hyperosmolar dehydration produced by higher doses or more frequent administration of mannitol may not provide additional advantage in terms of interhemispheric volume relationships or may even be harmful.11
The mechanism or mechanisms whereby mannitol infusions reduced the water content of edematous brain tissue after focal ischemic injury cannot be discerned directly from the results of this study. However, several possibilities emerge from a brief review of the relevant literature. Physical redistribution of the vasogenic component of ischemic edema from the core of the lesion into the relatively intact periphery through the extracellular space or intracerebral perivascular channels is one obvious possibility.32 It is well documented, for example, that in experimental ischemia followed by reperfusion33 and in experimental focal cold injury,34 hydrostatic pressure gradients may propel fluid from the edema source (lesion core) into the "perilesion" tissues. Once redistributed peripherally, edema fluid could be cleared through transendothelial osmotic gradients.35 Furthermore, it has been postulated that vessels in perilesion tissues may have higher hydraulic conductivities and may therefore clear water from the extracellular space even more effectively than normal vessels in response to osmotic gradients.36 If the rate of edema clearance by a perilesion route were to exceed the rate of new edema generation within the lesion core, net reduction in water content of the edematous tissue could result. This speculative mechanism of edema clearance requires experimental validation.
Another perspective from which to view the effect of mannitol infusions on the water content of edematous brain is to consider the effect of osmotic diuresis on the body's interstitial fluid compartment. Whereas the normal BBB regulates fluid flux to and from the interstitial space35 and intact brain cells posses highly efficient mechanisms for maintaining their water contents in the setting of dehydration and hyperosmolality,37 38 the status of water associated with an infarct may be more labile. To the extent that infarcted brain tissue takes on the characteristics of the general interstitial fluid space of the body (a high-sodium-content fluid no longer segregated by limiting membranes),39 it may be disproportionately affected by diuretic volume contraction compared with brain regions with intact volume regulatory mechanisms. The converse effect preferential increase of volume of damaged brain tissue secondary to expansion of the interstitial fluid compartment with isotonic saline infusions has been well documented.40 All agents used in osmotic therapy exert a potent generalized diuretic effect in addition to producing blood-brain osmotic gradients. While diuresis may not be necessary for and in fact is separable from the acute intracranial pressure–reducing effect of a mannitol bolus,41 42 gradual systemic dehydration with a proportionately greater impact on damaged, edematous tissue may be the basis for the observed effect of repeated mannitol infusions in this study.
Failure to detect evidence of a "rebound effect" in animals receiving multiple-dose mannitol in this study may reflect specific features of the experimental design. First, the timing of analysis of brain water content 24 or 48 hours after ischemia and 4 hours after the last dose of mannitol was chosen in an attempt to assess the net effect of mannitol infusions at a point in the evolution of ischemic brain edema at which previous studies in our laboratory, as well as those of other investigators using similar small-animal stroke models, have demonstrated that edema formation approaches a maximum value.23 It is certainly possible that at earlier or more delayed time points analysis of the tissue may have revealed the appearance of edema exacerbation. Similarly, it is possible that rebound elevations of brain tissue pressure would have been observed at earlier or later time points. Second, the rodent model used in this study is that of a large (15% increase of hemispheric volume at the point of maximum swelling) but not truly massive hemispheric stroke as may be encountered clinically. The model was chosen because of the low variability of the infarct volume produced by the surgical preparation and the well-characterized course of ischemic edema.20 22 23 Intracerebral fluid dynamics may be different when a lesion involves a larger percentage of hemispheric volume or when it interrupts the interstitial pathways leading to the ventricular or subarachnoid CSF. The latter have been implicated as important routes for the clearance of vasogenic edema.32 43 Third, all animals used in this study had a negative fluid balance consequent to mannitol infusions, as indicated by both the substantial loss of total body weight and development of hypernatremia over the course of 24 hours. In contrast, other studies that have reported exacerbation of vasogenic cerebral edema12 or late increases in intracranial pressure9 13 after multiple-dose mannitol infusions were either followed by fluid replacement with net positive fluid balance or total fluid balance was not reported. If a significant aspect of the therapeutic effect of a multiple-dose mannitol regimen is related to dehydration per se, then it is likely that volumetric replacement of diuretic fluid losses will offset the effect.
In conclusion, the results of this study support the concept that repeated mannitol infusions can reduce the water content of damaged brain regions. Reduction in tissue water content in experimental cortical infarction was associated with reduced tissue pressure within the damaged hemisphere. Our findings are consistent with those of other investigators who have observed reduction in the water content of damaged brain parenchyma after both acute30 and repeated28 29 doses of osmotically active solutions. This effect of repeated mannitol infusions on brain tissue water is potentially important clinically because the water content of the parenchyma constitutes the majority of volume within the rigid and essentially nondistensible cranial container. Caution is of course warranted in extending these results to strategies for clinical intervention. Dehydration of damaged brain parenchyma is only one possible therapeutic action of mannitol.17 18 19 Moreover, any management strategy for brain edema that results in systemic dehydration will be limited by the potentially adverse effects of dehydration on blood rheology and organ perfusion.44 45 However, it should be emphasized that the magnitude of systemic dehydration associated with potentially important clinical effects (on either the intracranial pressure-volume relationship or degree of midline shift) is not established and may not be large.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Institutes of Health grants NS-25545, NS-28995, and NS-35147 and by a career development award from the National Stroke Association (Dr Paczynski).
Received March 24, 1997; accepted April 17, 1997.
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