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Neurosurgery. Author manuscript; available in PMC 2013 July 30.
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Neurosurgery. 2012 May ; 70(5): 1215–1219. 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
Background—Mannitol 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.
Objective—To test the hypothesis that mannitol acts by lowering blood viscosity leading to
reflex vasoconstriction and a fall in cerebral blood volume (CBV).
Methods—We 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.
Results—CBV 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.
Conclusion—A 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 mannitol’s 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.

Our primary objective was to test whether mannitol acutely lowers CBV over a similar time frame as the fall in hemispheric volume.3. ICP was monitored continuously using an intrparenchymal device (Integra™ Camino® Intracranial Pressure Monitoring Kit. Plainsboro. 4 The technique employed in those studies could not differentiate whether the observed response was due to a fall in brain water or CBV. Mannitol (20%) was administered intravenously by intermittent boluses (starting with a dose of 1 gm/kg). the mechanism by which mannitol produces its effect on brain volume and ICP remain poorly understood. Clinical management In all patients. Page 2 ultimately herniation. cerebral edema and midline shift. Measurements of serum electrolytes. NIH-PA Author Manuscript Despite its widespread use and proven effectiveness in lowering ICP. The Human Research Protection Office and Radioactive Drugs Research Committee of Washington University approved the study. . Non-surgical treatment options are limited and mannitol has traditionally been the mainstay of medical therapy for intracranial hypertension in patients with head injury. Author manuscript. The effect of osmotic agents on CBV has never been assessed in humans. osmolality. fluid balances were assessed frequently. The patients were treated in a consistent manner by a single neurointensive care team. we measured cerebral blood flow (CBF). In a convenience sample of head injury already receiving osmotic therapy to treat intracranial hypertension. In order to address this unresolved question. and intravenous fluids were adjusted in order to keep the overall fluid balance even and maintain normal intravascular volume. CBV and oxygen metabolism (CMRO2) before and after a bolus of 1 g/Kg of mannitol. Diringer et al. either by raising blood pressure 1 or by reducing blood viscosity. Patients were weighed daily. Two potential explanations have been proposed.5mg/dl).05. NIH-PA Author Manuscript 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. Based on our prior measurements of CBV 5. inability to maintain an adequate airway or manage secretions. written informed consent was obtained from a legally authorized surrogate. Dose and timing were adjusted based on the ICP response. Neurosurgery. cardiac ischemia. 6 we calculated that in a sample size of 6 patients. we chose to measure CBV directly using 15O PET imaging. NJ) and intracranial NIH-PA Author Manuscript 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. and the osmotic gap were performed two to four times a day during osmotic therapy. a two-tailed Wilcoxon rank sum test will give us 80% power to detect a 10% change in CBV with an alpha= 0. Integra. Intubation was performed in patients with marked impairment of consciousness (typically GCS <9). which induce reflex vasoconstriction 2. and pregnancy. available in PMC 2013 July 30. All patients were ≥ 18 years of age. The second theory contends that mannitol acts by directly reducing brain water. Exclusion criteria included renal failure (serum creatinine >1. congestive heart failure. One theory argues that mannitol lowers ICP by reducing cerebral blood volume (CBV). We previously demonstrated that hemispheric volume falls one hour after administration of 1 gm/Kg of 20% mannitol to patients with ischemic.

A neurointensivist was present throughout the study. 9 Regional CBV was measured using a brief inhalation of 15O-labeled carbon monoxide.10. The median admission GCS was 6. Results Six patients with TBI were studied. midline shift < 5 mm. every effort was made to maintain a constant physiological state. a p < 0. Throughout the PET studies. cisterns present.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). and/or no high. Heart rate. During the study the only intervention directed toward ICP management was mannitol administration. Baseline measurements of GCS. Regional CBF was measured by bolus injection of 15O-labeled water using an adaptation of the Kety autoradiographic method. Because of the low number of subjects. physiologic data were recorded. All scans were calibrated for conversion of PET counts to quantitative radiotracer concentrations. Patients with TBI had their admission CT scans scored according to the Marshall criteria.8. Author manuscript. NIH-PA Author Manuscript Each scan was acquired in the two-dimensional mode. At the time of each image acquisition.05 was considered statistically significant. CBV. 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. blood pressure and CPP were continuously monitored and recorded every five minutes. osmolality.12 Quantitative measurements of arterial oxygen content (CaO2) were measured by oximetry. California). One hour after beginning the infusion. these analyses were considered exploratory and uncorrected p values are reported. Admission CT scans were classified as Marshall Grade 2 (diffuse injury. . PET imaging was repeated and GCS measured again.or mixed-density Neurosurgery. 11 while CMRO2 and oxygen extraction fraction (OEF) were derived from the CBF and CBV measurements and an inhalation of 15O-labeled oxygen. One g/Kg of 20% mannitol was then infused over 15 minutes. All PET scans for each patient were co-registered and aligned to the initial baseline CBF study using Automated Image Registration software (AIR. An individual transmission scan was obtained and used for subsequent attenuation correction of emission scan data. other continuous clinical and physiological variables and PET measurements were compared using the Wilcoxon rank-sum test. Roger Woods. NIH-PA Author Manuscript Data Analysis The primary outcome was the change in global CBV from before to after mannitol administration. University of California. Diringer et al. Serum osmolality and electrolytes were measured again four hours after completion of mannitol infusion. Los Angeles. and CMRO2. None of the patients received vasopressors and no interventions directed at changing blood pressure were used. Similarly. and NIH-PA Author Manuscript electrolytes were obtained and PET imaging performed to measure CBF. Page 3 Study Protocol The study was timed so that administration of mannitol between PET measurements coincided with treatment of elevated ICP. as previously described 8. CBV was compared before and after using the Wilcoxon rank-sum test. and all ongoing therapies were continued throughout the duration of the study. available in PMC 2013 July 30. Their clinical characteristics are summarized in Table 1.

but none in the past six hours. NIH-PA Author Manuscript The second proposes that mannitol acts through altering blood rheology. due in part to differing mechanisms of injury.1 mm Hg (p< 0. mannitol produced a parallel change in brain water (measured by CT density) and ICP. CBV (measured by laser Doppler flowmetry) increased following mannitol23. in part by increasing red cell deformability. This effect appears to be independent of any changes in hematocrit due to hemodilution. ICP fell from 21. Page 4 lesion >25 cc) in two cases. we did not assess other modulators of cerebrovascular tone.2 ml/100g before and after mannitol (Table 2).and dose-dependent fashion following mannitol administration 22. OEF and CMRO2 did not significantly change.7 ± 5. which then raises CBF and improves oxygen delivery.16 A reduction in brain volume may occur through a reduction in CSF. which lead to autoregulatory vasoconstriction. In normal monkeys.75 – 1. our measurements at 1-hour might miss the response. NIH-PA Author Manuscript CBV was 4. autoregulation or response to hyperventilation and hypoxia in our patients. available in PMC 2013 July 30.1 ± 0. One argues that a bolus of mannitol produces acute intravascular volume expansion and elevation in blood pressure. Two factors must be considered when interpreting our results. All were intubated and receiving osmotic therapy with mannitol to treat elevated intracranial pressure.4 and 4. Grade 5 evacuated mass lesion in three.028.5 ± 4. If this were the case. Mannitol doses of 0. In normal rats. Studies in humans have been limited to pathological states. This theory states that mannitol reduces blood viscosity. CBV (measured with MRI) increased in a time. In intra-operative biopsies of white matter taken from TBI patients who were already receiving mannitol.15 According to the Monro-Kellie doctrine. Such a brief response. is unlikely to account for a clinically important response. in order for ICP to fall. The magnitude of the response is determined by the dose. A fall in ICP was observed in every patient (Figure 2).9 to 13. mannitol dosing and correction of mannitol-induced diuresis. leading to a reflex vasoconstriction and a fall in CBV. Discussion The ability of osmotic agents to reduce ICP is undisputed. CPP and CBF tended to rise after mannitol. First. Two theories have been proposed to explain how mannitol could produce a fall in CBV.13 baseline level of ICP 14 and infusion rate. or brain blood volume (CBV). Diringer et al.21 Our results do not support the hypotheses that mannitol acts by reducing cerebral blood volume. Figure 1). The alternative hypothesis for mannitol’s ability to lower ICP argues that it reduces brain water. reducing CBV. there must be a reduction in intracranial volume. and Grade 6 non- evacuated mass lesion > 25 cc in one. that is no longer detectable at a time when both brain volume and ICP NIH-PA Author Manuscript are still falling.2 ± 0.61 to 77.17–19 However. Other studies in animals have noted similar findings. Second. In a cat model of brain edema. Animal models of disease states have yielded conflicting results.96% (wet/dry weight method) in normal rabbits 25.25 g/kg reduced ICP and lowered brain water from 79. brain tissue volume (water). This is based on the observation that mannitol produced a rapid constriction of both arterioles and venules on the surface of the brain 20. At the same time. our data indicate that boluses of mannitol do not consistently raise blood pressure. brain Neurosurgery. Author manuscript. although blood pressure was unchanged. . 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. Studies in dogs using labeled red blood cells found an early 20–25% increase in CBV 1–3 minutes after mannitol bolus 24. the vasoconstrictive response to mannitol may occur within the first few minutes after mannitol administration and be transient.

3% following administration of a single dose of 0. [PubMed: 1588618] 8. [PubMed: 11739839] 5. et al. Neurology. et al. J Nucl Med. J Neurotrauma. Manno EM. Raichle ME. Raichle ME. No reduction in cerebral metabolism as a result of early NIH-PA Author Manuscript moderate hyperventilation following severe traumatic brain injury. Powers WJ. Muizelaar JP. Markham J. Mar. Neurosurgery. Derdeyn CP. Adams RE. Page 5 water content fell from 80. Mintun MA. and kinetics and determine their relationship to changes in brain water and volume and outcome. Becker DP. Jan. Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke. Yundt K. Using 15O PET we found that 1 g/Kg of 20% mannitol does not lower CBV. Author manuscript. 1987. [PubMed: 10616076] 6. may better explain mannitol’s ability to NIH-PA Author Manuscript lower ICP. The diagnosis of head injury requires a classification based on computed axial tomography. Herscovitch P. Brain blood flow measured with intravenous H2(15)O. and suggest that another mechanism. I. 1983.28 g/kg of mannitol 26. 1983. CT brain density (used to measure brain water content) rose progressively following doses of 1–2 g/kg of mannitol 27. The effects of mannitol on cerebral edema after large hemispheric cerebral infarct. 59:822–828. [PubMed: 6413661] 3. J Neurosurg. 24(9):790–798. 24(9):782–789. Martin WR. Coley I. Neurology. II. Marshall LF. et al. Jan. 1983. Cerebral perfusion pressure: a hemodynamic mechanism of mannitol and the postmannitol hemogram. [PubMed: 11794590] 7. In brain tumor patients. Acknowledgments This work was support by NIH NS035966. doses. Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes. such as a reduction in brain water. et al. Markham J. Manno EM. J Neurosurg. Diringer et al. 1999 52(3):583–587. Further study of osmotic therapy is needed to better compare agents. Rosner MJ. Diringer MN. Regional cerebrovascular and metabolic effects of hyperventilation after severe traumatic brain injury. [PubMed: 6604139] 9. Herscovitch P. The data do not address what occurs in mannitol naive patients. J Nucl Med. [PubMed: 10025792] 4. NIH-PA Author Manuscript While these data address the mechanistic question regarding how mannitol reduces brain volume. Videen TO. Klauber MR. 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). Yundt K. Reference List 1. Implementation and validation. Brain blood flow measured with intravenous H2(15)O. Wei EP. 2002 96(1):103–108. [PubMed: 6604140] Neurosurgery. important questions remain unanswered. . Videen TO. 2001. 21(2):147–156. Theory and error analysis. 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. [PubMed: 3116451] 2. Kontos HA. Diringer MN. 1992 9 (Suppl 1):S287–292. Feb. 57(11):2120–2122.1 to 75. Zazulia AR. J Neurosurg. Videen TO. as the subjects were studied after they had already received mannitol. Diringer MN. available in PMC 2013 July 30. nor do they address the effects of multiple doses. 2000 92(1):7– 13. Marshall SB.

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Intracranial pressure (ICP) and cerebral blood volume (CBV) before and after 1g/Kg of 20% mannitol in patients with head injury. Page 7 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. Diringer et al. . available in PMC 2013 July 30. Author manuscript. post stroke edema and intracerebral hemorrhage. NIH-PA Author Manuscript Neurosurgery.

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. NIH-PA Author Manuscript Neurosurgery. Diringer et al. available in PMC 2013 July 30. . Author manuscript. Page 8 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 2.

range) 6 (3–8) Midline shift (mm. white/black 5/1 Admission GCS (median. Author manuscript.9 Marshall grade Diffuse type 1 0 Diffuse type 2 2 Diffuse type 3 0 Diffuse type 4 0 5 . . Diringer et al.5 ± 3.Evacuated mass lesion 3 6 . available in PMC 2013 July 30. female (n) 1 Race.2 ± 11. Page 9 Table 1 Admission Clinical Characteristics NIH-PA Author Manuscript Head injury Number of subjects 6 Age. mean ± SD) 3. years (mean ± SD) 30.8 SD=standard deviation NIH-PA Author Manuscript Neurosurgery.4 ± 1.9 Sex.Non-evacuated mass lesion 1 NIH-PA Author Manuscript Days to PET (mean ± SD) 3.

1** CPP# 76.2 MAP# 98.6 ± 10.8 42.2 ± 0.3 125 ± 33. .028 NIH-PA Author Manuscript Neurosurgery.1 ± 0.7 ± 5.3 ± 8.6 96.4 4. NIH-PA Author Manuscript * p < 0.8 ± 0.2 CMRO2+ 1.7 ICP # 21.4 1.2 ± 8.9 35.Mannitol CBF+ 40. Diringer et al.8 PaO2 113 ± 31.7 ± 4.7 ± 5. ** p < 0. available in PMC 2013 July 30.2 ± 5. Page 10 Table 2 Physiological values before and after mannitol NIH-PA Author Manuscript Traumatic Brian Injury (n=6) Baseline Post.0 + =ml/100g/min.9 13. ++ =ml/100g.7 ± 8. Author manuscript.5 ± 4.5 ± 4.2 CBV++ 4.8 PaCO2 34.05.9 82. # = mm Hg.8 ± 0.