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Neurosurgery. 2012 May ; 70(5): 12151219. doi:10.1227/NEU.0b013e3182417bc2.

Effect of Mannitol on Cerebral Blood Volume in Patients with

Head Injury
Michael N. Diringer, MD, FCCM1, Michael T. Scalfani, BS, MCI1, Allyson R. Zazulia, MD1,2,
Tom O. Videen, PhD1,2, Rajat Dhar, MD1, and William J Powers, MD3
1Departments of Neurology and Neurological Surgery, Washington University School of Medicine,

St. Louis MO
2Department of and Radiology, Neurology/Neurosurgery Intensive Care Unit, Washington
University School of Medicine, St. Louis MO
3Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina
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Abstract
BackgroundMannitol has traditionally been the mainstay of medical therapy for intracranial
hypertension in patients with head injury. We previously demonstrated that mannitol reduces brain
volume in patients with cerebral edema, although whether this occurs due to a reduction in brain
water, blood volume or both remains poorly understood.
ObjectiveTo test the hypothesis that mannitol acts by lowering blood viscosity leading to
reflex vasoconstriction and a fall in cerebral blood volume (CBV).
MethodsWe used 15O PET to study six patients with traumatic brain injuries requiring
treatment for intracranial hypertension. Cerebral blood flow (CBF), CBV and cerebral metabolic
rate for oxygen (CMRO2) were measured before and one hour after administration of 1.0 g/kg
20% mannitol.
ResultsCBV rose from 4.1 0.4 to 4.2 0.2 ml/100g (p=0.3) while ICP fell from 21.5 4.9
to 13.7 5.1 mm Hg (p< 0.003) after mannitol. Blood pressure, PaCO2, oxygen content, CBF and
CMRO2 did not change.
ConclusionA single bolus of 1 g/Kg of 20% mannitol does not acutely lower CBV. Another
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mechanism, such as a reduction in brain water, may better explain mannitols ability to lower ICP
and reduce mass effect.

Keywords
osmotic; mannitol; cerebral blood flow; cerebral blood volume

Introduction
Acute head injury is frequently complicated by edema and mass effect. This increase in
intracranial volume can elevate intracranial pressure (ICP), critically reduce cerebral
perfusion pressure (CPP) and lead to global ischemia. Additionally, focal edema and masses
induce pressure gradients across intracranial compartments that can lead to tissue shifts and

Corresponding Author: Michael N. Diringer, MD, FCCM, Washington University School of Medicine, Dept. of Neurology, Campus
Box 8111, 660 S Euclid Ave, St Louis, MO 63110, Phone: 314-362-2999, Fax: 314-362-0215, diringerm@wustl.edu.
The authors have no fother disclosures.
 Diringer et al. Page 2

ultimately herniation. Non-surgical treatment options are limited and mannitol has
traditionally been the mainstay of medical therapy for intracranial hypertension in patients
with head injury.
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Despite its widespread use and proven effectiveness in lowering ICP, the mechanism by
which mannitol produces its effect on brain volume and ICP remain poorly understood. Two
potential explanations have been proposed. One theory argues that mannitol lowers ICP by
reducing cerebral blood volume (CBV), either by raising blood pressure 1 or by reducing
blood viscosity, which induce reflex vasoconstriction 2. The second theory contends that
mannitol acts by directly reducing brain water. The effect of osmotic agents on CBV has
never been assessed in humans.

We previously demonstrated that hemispheric volume falls one hour after administration of
1 gm/Kg of 20% mannitol to patients with ischemic, cerebral edema and midline shift.3, 4
The technique employed in those studies could not differentiate whether the observed
response was due to a fall in brain water or CBV. In order to address this unresolved
question, we chose to measure CBV directly using 15O PET imaging. In a convenience
sample of head injury already receiving osmotic therapy to treat intracranial hypertension,
we measured cerebral blood flow (CBF), CBV and oxygen metabolism (CMRO2) before
and after a bolus of 1 g/Kg of mannitol. Our primary objective was to test whether mannitol
acutely lowers CBV over a similar time frame as the fall in hemispheric volume.
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Materials and Methods

Eligible patients
Traumatic brain injury (TBI) patients were eligible if they had a GCS score of 11 and were
receiving osmotic therapy for intracranial hypertension. Exclusion criteria included renal
failure (serum creatinine >1.5mg/dl), congestive heart failure, cardiac ischemia, and
pregnancy. All patients were 18 years of age. The Human Research Protection Office and
Radioactive Drugs Research Committee of Washington University approved the study;
written informed consent was obtained from a legally authorized surrogate.

Based on our prior measurements of CBV 5, 6 we calculated that in a sample size of 6

patients, a two-tailed Wilcoxon rank sum test will give us 80% power to detect a 10%
change in CBV with an alpha= 0.05.

Clinical management
In all patients, ICP was monitored continuously using an intrparenchymal device (Integra
Camino Intracranial Pressure Monitoring Kit, Integra, Plainsboro, NJ) and intracranial
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hypertension (ICP > 20 mm Hg) was treated using a step-wise approach. The initial step
consisted of sedation with benzodiazepines and opiates followed by intermittent boluses of
20% mannitol. Dose and timing were adjusted based on the ICP response.

The patients were treated in a consistent manner by a single neurointensive care team.
Intubation was performed in patients with marked impairment of consciousness (typically
GCS <9), inability to maintain an adequate airway or manage secretions. Mannitol (20%)
was administered intravenously by intermittent boluses (starting with a dose of 1 gm/kg).
Patients were weighed daily, fluid balances were assessed frequently, and intravenous fluids
were adjusted in order to keep the overall fluid balance even and maintain normal
intravascular volume. Measurements of serum electrolytes, osmolality, and the osmotic gap
were performed two to four times a day during osmotic therapy.

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Study Protocol
The study was timed so that administration of mannitol between PET measurements
coincided with treatment of elevated ICP. Baseline measurements of GCS, osmolality, and
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electrolytes were obtained and PET imaging performed to measure CBF, CBV, and
CMRO2. One g/Kg of 20% mannitol was then infused over 15 minutes. One hour after
beginning the infusion, PET imaging was repeated and GCS measured again. Heart rate,
blood pressure and CPP were continuously monitored and recorded every five minutes.
Serum osmolality and electrolytes were measured again four hours after completion of
mannitol infusion. During the study the only intervention directed toward ICP management
was mannitol administration. None of the patients received vasopressors and no
interventions directed at changing blood pressure were used. Patients with TBI had their
admission CT scans scored according to the Marshall criteria.7

PET Methods
All patients were studied on the same Siemens CTI ECAT EXACT HR 47 PET Scanner
located within the Neurology-Neurosurgery Intensive Care Unit (NNICU). A
neurointensivist was present throughout the study, and all ongoing therapies were continued
throughout the duration of the study. Throughout the PET studies, every effort was made to
maintain a constant physiological state. At the time of each image acquisition, physiologic
data were recorded.
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Each scan was acquired in the two-dimensional mode. An individual transmission scan was
obtained and used for subsequent attenuation correction of emission scan data. All scans
were calibrated for conversion of PET counts to quantitative radiotracer concentrations, as
previously described 8.

Regional CBF was measured by bolus injection of 15O-labeled water using an adaptation of
the Kety autoradiographic method.8, 9 Regional CBV was measured using a brief inhalation
of 15O-labeled carbon monoxide,10, 11 while CMRO2 and oxygen extraction fraction (OEF)
were derived from the CBF and CBV measurements and an inhalation of 15O-labeled
oxygen.12 Quantitative measurements of arterial oxygen content (CaO2) were measured by
oximetry.

All PET scans for each patient were co-registered and aligned to the initial baseline CBF
study using Automated Image Registration software (AIR, Roger Woods, University of
California, Los Angeles, California). An image mask was created for global measurements
that included the brain below the superior sagittal sinus down to the level of the pineal
gland.
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Data Analysis
The primary outcome was the change in global CBV from before to after mannitol
administration. Because of the low number of subjects, CBV was compared before and after
using the Wilcoxon rank-sum test; a p < 0.05 was considered statistically significant.
Similarly, other continuous clinical and physiological variables and PET measurements were
compared using the Wilcoxon rank-sum test; these analyses were considered exploratory
and uncorrected p values are reported.

Results
Six patients with TBI were studied. Their clinical characteristics are summarized in Table 1.
The median admission GCS was 6. Admission CT scans were classified as Marshall Grade 2
(diffuse injury, cisterns present, midline shift < 5 mm, and/or no high- or mixed-density

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lesion >25 cc) in two cases, Grade 5 evacuated mass lesion in three, and Grade 6 non-
evacuated mass lesion > 25 cc in one. All were intubated and receiving osmotic therapy with
mannitol to treat elevated intracranial pressure.
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CBV was 4.1 0.4 and 4.2 0.2 ml/100g before and after mannitol (Table 2). At the same
time, ICP fell from 21.5 4.9 to 13.7 5.1 mm Hg (p< 0.028, Figure 1). A fall in ICP was
observed in every patient (Figure 2). CPP and CBF tended to rise after mannitol, although
blood pressure was unchanged. OEF and CMRO2 did not significantly change.

Discussion
The ability of osmotic agents to reduce ICP is undisputed. The magnitude of the response is
determined by the dose,13 baseline level of ICP 14 and infusion rate.15 According to the
Monro-Kellie doctrine, in order for ICP to fall, there must be a reduction in intracranial
volume.16 A reduction in brain volume may occur through a reduction in CSF, brain tissue
volume (water), or brain blood volume (CBV).

Two theories have been proposed to explain how mannitol could produce a fall in CBV. One
argues that a bolus of mannitol produces acute intravascular volume expansion and elevation
in blood pressure, which lead to autoregulatory vasoconstriction, reducing CBV.1719
However, our data indicate that boluses of mannitol do not consistently raise blood pressure.
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The second proposes that mannitol acts through altering blood rheology. This is based on the
observation that mannitol produced a rapid constriction of both arterioles and venules on the
surface of the brain 20. This theory states that mannitol reduces blood viscosity, in part by
increasing red cell deformability, which then raises CBF and improves oxygen delivery,
leading to a reflex vasoconstriction and a fall in CBV. This effect appears to be independent
of any changes in hematocrit due to hemodilution.21

Our results do not support the hypotheses that mannitol acts by reducing cerebral blood
volume. Other studies in animals have noted similar findings. In normal rats, CBV
(measured with MRI) increased in a time- and dose-dependent fashion following mannitol
administration 22. In a cat model of brain edema, CBV (measured by laser Doppler
flowmetry) increased following mannitol23. Studies in dogs using labeled red blood cells
found an early 2025% increase in CBV 13 minutes after mannitol bolus 24.

Two factors must be considered when interpreting our results. First, the vasoconstrictive
response to mannitol may occur within the first few minutes after mannitol administration
and be transient. If this were the case, our measurements at 1-hour might miss the response.
Such a brief response, that is no longer detectable at a time when both brain volume and ICP
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are still falling, is unlikely to account for a clinically important response. Second, we did not
assess other modulators of cerebrovascular tone, autoregulation or response to
hyperventilation and hypoxia in our patients. If overall vascular reactivity were impaired
then it would be reasonable to expect that the response to changes in viscosity would be
compromised as well.

The alternative hypothesis for mannitols ability to lower ICP argues that it reduces brain
water. Mannitol doses of 0.75 1.25 g/kg reduced ICP and lowered brain water from 79.61
to 77.96% (wet/dry weight method) in normal rabbits 25. In normal monkeys, mannitol
produced a parallel change in brain water (measured by CT density) and ICP. Animal
models of disease states have yielded conflicting results, due in part to differing mechanisms
of injury, mannitol dosing and correction of mannitol-induced diuresis. Studies in humans
have been limited to pathological states. In intra-operative biopsies of white matter taken
from TBI patients who were already receiving mannitol, but none in the past six hours, brain

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water content fell from 80.1 to 75.3% following administration of a single dose of 0.28 g/kg
of mannitol 26. In brain tumor patients, CT brain density (used to measure brain water
content) rose progressively following doses of 12 g/kg of mannitol 27.
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While these data address the mechanistic question regarding how mannitol reduces brain
volume, important questions remain unanswered. The data do not address what occurs in
mannitol naive patients, as the subjects were studied after they had already received
mannitol, nor do they address the effects of multiple doses.

Our data indicate that a bolus of mannitol does not reduce cerebral blood volume and
suggest that the impact of mannitol on ICP is mediated by another mechanism such as a fall
in brain water. Further study of osmotic therapy is needed to better compare agents, doses,
and kinetics and determine their relationship to changes in brain water and volume and
outcome.

Conclusion
We sought to test the hypothesis that mannitol reduces ICP in patients with traumatic brain
injuries and intracranial hypertension by lowering cerebral blood volume (CBV). Using 15O
PET we found that 1 g/Kg of 20% mannitol does not lower CBV, and suggest that another
mechanism, such as a reduction in brain water, may better explain mannitols ability to
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lower ICP.

Acknowledgments
This work was support by NIH NS035966.

Reference List
1. Rosner MJ, Coley I. Cerebral perfusion pressure: a hemodynamic mechanism of mannitol and the
postmannitol hemogram. Neurosurgery. 1987; 21(2):147156. [PubMed: 3116451]
2. Muizelaar JP, Wei EP, Kontos HA, Becker DP. Mannitol causes compensatory cerebral
vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg. 1983;
59:822828. [PubMed: 6413661]
3. Manno EM, Adams RE, Derdeyn CP, Powers WJ, Diringer MN. The effects of mannitol on cerebral
edema after large hemispheric cerebral infarct. Neurology. Feb; 1999 52(3):583587. [PubMed:
10025792]
4. Videen TO, Zazulia AR, Manno EM, et al. Mannitol bolus preferentially shrinks non-infarcted brain
in patients with ischemic stroke. Neurology. 2001; 57(11):21202122. [PubMed: 11739839]
5. Diringer MN, Yundt K, Videen TO, et al. No reduction in cerebral metabolism as a result of early
NIH-PA Author Manuscript

moderate hyperventilation following severe traumatic brain injury. J Neurosurg. Jan; 2000 92(1):7
13. [PubMed: 10616076]
6. Diringer MN, Videen TO, Yundt K, et al. Regional cerebrovascular and metabolic effects of
hyperventilation after severe traumatic brain injury. J Neurosurg. Jan; 2002 96(1):103108.
[PubMed: 11794590]
7. Marshall LF, Marshall SB, Klauber MR, et al. The diagnosis of head injury requires a classification
based on computed axial tomography. J Neurotrauma. Mar; 1992 9 (Suppl 1):S287292. [PubMed:
1588618]
8. Herscovitch P, Markham J, Raichle ME. Brain blood flow measured with intravenous H2(15)O. I.
Theory and error analysis. J Nucl Med. 1983; 24(9):782789. [PubMed: 6604139]
9. Raichle ME, Martin WR, Herscovitch P, Mintun MA, Markham J. Brain blood flow measured with
intravenous H2(15)O. II. Implementation and validation. J Nucl Med. 1983; 24(9):790798.
[PubMed: 6604140]

Neurosurgery. Author manuscript; available in PMC 2013 July 30.

 Diringer et al. Page 6

10. Martin WR, Powers WJ, Raichle ME. Cerebral blood volume measured with inhaled C15O and
positron emission tomography. J Cereb Blood Flow Metab. 1987; 7(4):421426. [PubMed:
3497162]
NIH-PA Author Manuscript

11. Videen TO, Perlmutter JS, Herscovitch P, Raichle ME. Brain blood volume, flow, and oxygen
utilization measured with 15O radiotracers and positron emission tomography: revised metabolic
computations. J Cereb Blood Flow Metab. 1987; 7(4):513516. [PubMed: 3497165]
12. Mintun MA, Raichle ME, Martin WR, Herscovitch P. Brain oxygen utilization measured with
O-15 radiotracers and positron emission tomography. J Nucl Med. 1984; 25(2):177187.
[PubMed: 6610032]
13. James HE. Methodology for the control of intracranial pressure with hypertonic mannitol. Acta
Neurochir (Wien). 1980; 51(34):161172. [PubMed: 6768226]
14. McGraw CP, Alexander E Jr, Howard G. Effect of dose and dose schedule on the response of
intracranial pressure to mannitol. Surg Neurol. 1978; 10(2):127130. [PubMed: 705588]
15. Roberts PA, Pollay M, Engles C, Pendleton B, Reynolds E, Stevens FA. Effect on intracranial
pressure of furosemide combined with varying doses and administration rates of mannitol. J
Neurosurg. Mar; 1987 66(3):440446. [PubMed: 3102698]
16. Monro, A. Observations on the Structure and Functions of the Nervous System. Edinburgh: Creech
and Johnson; 1783.
17. Rosner MJ. Introduction to cerebral perfusion pressure management. Neurosurg Clin N Am. Oct;
1995 6(4):761773. [PubMed: 8527917]
18. Rosner MJ, Coley I. Cerebral perfusion pressure: a hemodynamic mechanism of mannitol and the
NIH-PA Author Manuscript

postmannitol hemogram. Neurosurgery. Aug; 1987 21(2):147156. [PubMed: 3116451]

19. Rosner MJ, Rosner SD, Johnson AH. Cerebral perfusion pressure: management protocol and
clinical results. J Neurosurg. Dec; 1995 83(6):949962. [PubMed: 7490638]
20. Muizelaar JP, van der Poel HG, Li ZC, Kontos HA, Levasseur JE. Pial arteriolar vessel diameter
and CO2 reactivity during prolonged hyperventilation in the rabbit. J Neurosurg. Dec; 1988 69(6):
923927. [PubMed: 3142972]
21. Burke AM, Quest DO, Chien S, Cerri C. The effects of mannitol on blood viscosity. J Neurosurg.
Oct; 1981 55(4):550553. [PubMed: 6792325]
22. Lin W, Paczynski RP, Kuppusamy K, Hsu CY, Haacke EM. Quantitative measurements of
regional cerebral blood volume using MRI in rats: effects of arterial carbon dioxide tension and
mannitol. Magn Reson Med. Sep; 1997 38(3):420428. [PubMed: 9339444]
23. Inao S, Kuchiwaki H, Wachi A, et al. Effect of mannitol on intracranial pressure-volume status and
cerebral haemodynamics in brain oedema. Acta Neurochir Suppl (Wien). 1990; 51:401403.
[PubMed: 2128581]
24. Ravussin P, Archer DP, Meyer E, Abou-Madi M, Yamamoto L, Trop D. The effects of rapid
infusions of saline and mannitol on cerebral blood volume and intracranial pressure in dogs. Can
Anaesth Soc J. Sep; 1985 32(5):506515. [PubMed: 3930050]
25. Donato T, Shapira Y, Artru A, Powers K. Effect of mannitol on cerebrospinal fluid dynamics and
NIH-PA Author Manuscript

brain tissue edema. Anesth Analg. Jan; 1994 78(1):5866. [PubMed: 8267182]
26. Nath F, Galbraith S. The effect of mannitol on cerebral white matter water content. J Neurosurg.
Jul; 1986 65(1):4143. [PubMed: 3086519]
27. Cascino T, Baglivo J, Conti J, Szewczykowski J, Posner JB, Rottenberg DA. Quantitative CT
assessment of furosemide- and mannitol-induced changes in brain water content. Neurology. Jul;
1983 33(7):898903. [PubMed: 6306506]

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Figure 1.
Intracranial pressure (ICP) and cerebral blood volume (CBV) before and after 1g/Kg of 20%
mannitol in patients with head injury, post stroke edema and intracerebral hemorrhage.
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Figure 2.
Changes in intracranial pressure (ICP) and cerebral blood volume (CBV) in each individual
patient 1 hour after administration of 1 g/Kg of 20% mannitol.
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Table 1
Admission Clinical Characteristics
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Head injury

Number of subjects 6
Age, years (mean SD) 30.2 11.9
Sex, female (n) 1
Race, white/black 5/1
Admission GCS (median, range) 6 (38)
Midline shift (mm, mean SD) 3.5 3.9
Marshall grade
Diffuse type 1 0
Diffuse type 2 2
Diffuse type 3 0
Diffuse type 4 0
5 - Evacuated mass lesion 3
6 - Non-evacuated mass lesion 1
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Days to PET (mean SD) 3.4 1.8

SD=standard deviation
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Table 2
Physiological values before and after mannitol
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Traumatic Brian Injury (n=6) Baseline Post- Mannitol

CBF+ 40.2 8.8 42.7 8.2

CBV++ 4.1 0.4 4.2 0.2

CMRO2+ 1.8 0.4 1.8 0.2

MAP# 98.2 5.6 96.3 8.7

ICP # 21.5 4.9 13.7 5.1**

CPP# 76.7 5.9 82.6 10.8

PaCO2 34.5 4.9 35.7 4.8

PaO2 113 31.3 125 33.0

+
=ml/100g/min,
++
=ml/100g,
#
= mm Hg,
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*
p < 0.05,
**
p < 0.028
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