Mannitol Infusion to Reduce Intraocular Pressure

DANIEL I. WEISS, M.D., New York; ROBERT N. SHAFFER, M.D., and

BURTON L. WISE, M.D., San Francisco

In 1904, Cantonnet recommended les sub-
stances osmotiques (sodium chloride, lactose)
in the treatment of glaucoma.1 Since then a
number of osmotic agents have been used,
with more or less success, to lower both cere-
brospinal fluid pressure and intraocular pres-
sure.2-4 Recently, intravenous hypertonic
urea has been effectively used.5,6
Mannitol, a 6-carbon hexahydric alcohol,
has been employed fairly extensively as an
Submitted forpublication March 2, 1962.
USPHS Special Fellow in Ophthalmology (Dr.
Weiss).
From the Departments of Ophthalmology and
Neurological Surgery, University of California
School of Medicine.
osmotic diuretic.7,8 Recent experimental and
clinical studies have demonstrated that hyper-
tonic mannitol solutions are effective in
lowering cerebrospinal fluid pressure and de-
creasing brain mass.9,12,20 Mannitol is stable
in solution, inert, and nontoxic, and its distri-
bution is limited to the extracellular fluid
compartment.8-10 These facts indicated that
hypertonic mannitol might be an excellent
agent for the reduction of intraocular pres-
sure.
Methods and Materials
Ten consecutive patients who received mannitol
infusions are included in this study. The group is
comprised of 2 patients from the neurosurgical
service and 8 patients from the ophthalmological

Table 1.—Effect of Hypertonic Mannitol Infusion upon Intraocular Pressure

t Serum
Intraocular Osmolality
Pressure (mOsm per
(mm. Hg) liter)
Patient
Dose of Before After
No. Age Sex Diagnosis Previous Med. Mannitol Mannitol Mannitol Before After

1 37 Malignant subcortical None 3.2gm/kg O.D. 17 Soft 287 329

glioma (papilledema) O.S. 17 Soft
2 43 F Olioblastoma multi¬ None 3gm/kg O.D. 21 5 286 319
forme (papilledema) O.S.19 Soft
3 57 Angle-closure glaucoma, Miotics 2.2gm/kg O.D. 57 <17 296 318
O.D. I. V. acetazolamide O.S.15 5
4 19 F Secondary glaucoma, Miotics, epineph- 2.1gm/kg O.D. 84 <17
O.U. rineand acetazol¬ O.S. 72 <17
amide
64 F Malignant glaucoma, Pilocarpine, aceta¬ ~2.1gm/kg O.D. 58 294 324
O.D. zolamide O.S.
6 57 F Chronic angle-closure Miotics, acetazolamide 1.3gm/kg O.D. 22 7 299 311
glaucoma, O.D. O.S.10 7
7 78 F Angle-closure glau¬ None 2.1gm/kg O.D. 88 Î51 296 308
coma, O.D. O.S. 23
55 F Retinal detachment, None <2gm/kg O.S.
O.D. O.D.
"normo- "Soft"
tensive"
9 33 M Hemorrliagic glaucoma, Miotics, epineph- 2.1gm/kg O.D. 12 Soft
O.S. rine, and aceta¬ O.S. 44 29
zolamide
10 42 M Central serous retin¬ None 1.1 gm/kg O.D. 19 12
opathy, O.D. O.S. 17 10

t Normal values were 289±4 mOsm per liter.

Î Pressure dropped to 15 mm. Hg after miotics and I.V. acetazolamide.

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 Fig. 1.—The effect of
20% mannitol infusion
upon both the intraocular
pressure and the cerebro-
spinal fluid pressure.
service, representing a diversified and instructive
group (Table 1).
An infusion of 20% mannitol in water * was
given by intravenous drip. Infusion time varied
from 25 minutes to 1 hour and 45 minutes ; the total
dosage varied from 1.1 to 3.2 gm. per kilogram.
The patients were observed carefully and questioned
concerning symptoms that might relate to the infu¬
sion. Patients who were immediately preoperative
had indwelling catheters placed. Serum osmolality
changes were determined by the freezing-point de¬
pression technique.
Report of Cases
Cases 1, 2.—These neurosurgical patients were
included in the study to demonstrate and correlate
the effect of increasing serum osmolality on both
the cerebrospinal fluid pressure and the intraocular
pressure. Figure 1 illustrates the dramatic fall in
*
Supplied by Martin Roberts, Ph.D., Clinical Re-
search Division of Don Baxter, Inc., Glendale, Calif.
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cerebrospinal fluid pressure and the associated fall
in intraocular pressure (Case 2). These were our
first patients, and 3 gm. per kilogram was adminis¬
tered. We then realized that this dosage rate was
probably unnecessarily high, and the dosage was
subsequently reduced.
Case 3.—This 57-year-old white female entered
the hospital with a painful, red right eye. The cor¬
nea was hazy, the pupil semidilated, and intraocular
pressure was 58 mm. Hg. Gonioscopy revealed a
closed angle. Miotic drops were administered, and
intravenous acetazolamide (Diamox) was given to
no avail. Four hours later intraocular pressure was
57 mm. Hg. Mannitol infusion was begun, and
the tension was reduced to 17 mm. Hg when the
patient was brought to surgery. At the time of
surgery the surgeon noted that the eye was even
softer. Thermal sclerectomy was performed.
Comment.—Acute angle-closure glaucoma
that does not respond to miotics and acetazol¬
amide is probably the most frequent indica¬
tion for osmotic therapy. Mannitol infusion
Fig. 2.—The effect of
20% mannitol infusion
upon acute angle-closure
glaucoma which had not
responded to pilocarpine
and acetazolamide ther¬
apy.

here lasted 1 hour and 45 minutes, accounting
for the relatively slow drop in intraocular
pressure (Fig. 2). We now recommend a
faster infusion rate.
Case 4.—This 19-year-old diabetic girl had sec¬
ondary glaucoma in both eyes subsequent to several
congenital cataract procedures in both eyes. On
demecarium bromide (Humorsol), /-epinephrine
(Eppy*), and acetazolamide her tensions were 84
mm. Hg in the right eye, 72 mm. Hg in the left
eye. Mannitol infusion resulted in a dramatic fall
in intraocular pressure (Fig. 3).
Comment.—This girl's urine gave a 4 plus
Benedict's reaction immediately after the
mannitol infusion. The resident surgeon
alertly but erroneously reasoned that the
mannitol might be giving the positive reac-
*
Barnes\p=m-\HindOphthalmic Products, Inc., Sun-
nyvale, Calif.
Fig. 4.—The response
of a malignant glaucoma
to 20% mannitol infusion.
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Fig. 3.—The effect of
20% mannitol infusion
upon a secondary glau¬
coma uncontrolled by
other medical therapy.
tion. Mannitol is the reduced form of man-
nose and therefore does not give a positive
test for reducing substances. However, the
possibility does remain that a diuresis may
carry sugar with it if the blood sugar level
is approaching the renal threshold.
Case 5.—This 64-year-old white female had a
chronic narrow-angle glaucoma of the right eye for
which an iridectomy was performed. At the time of
surgery her anterior chamber was shallow and ten¬
sion was 30 mm. Hg ; gonioscopically the angle was
closed except for a slit nasally. Two days post¬
operatively the eye became painful, and intraocular
pressure rose to 58 mm. Hg. The anterior chamber
was flat. Mannitol infusion was rapidly effective
(Fig. 4).
The nextmorning the intraocular pressure was
9 mm.Hg. The anterior chamber had re-formed.
Gonioscopy revealed the nasal angle to be open to
Grade 2, but the rest of the angle was occluded. A
 Fig. 5.—The response
of chronic angle-closure
glaucoma to 20% mannitol
infusion.
cataract section was made above, a spatula was
inserted across the anterior chamber, and an ante¬
rior synechialysis was performed below; the lens
was then removed intracapsularly. The
hyaloid face
was noted to be well back and concave.
Comment.—This represents a case of ma¬
lignant glaucoma, noteworthy in that hyper-
tonic mannitol administration re-formed the
anterior chamber. The intraocular tension
was still low 6 hours after the infusion, even
though the serum osmolality levels were re¬
turning to the baseline (see Figure). An
exciting possibility is raised: perhaps osmotic
therapy can interrupt the malignant cycle in
some cases of malignant glaucoma, thereby
abrogating the need for surgical intervention.
Case 6.—This 57-year-old white female intermit¬
tently saw halos around lights for several months.
The left eye had been blind for many years from
chronic angle-closure glaucoma. When the patient
was first seen the tension in the right eye was
poorly controlled on miotics and acetazolamide.
Gonioscopy revealed most of the angle to be closed
except for a small area where the angle appeared
slit-like. When she was hospitalized for surgery,
tension in her right eye was reduced from 35 to 22
mm. I lg. With the recollection of our recent malig¬
nant glaucoma case fresh in mind we administered
intravenous mannitol, both as a prophylactic and di¬
agnostic procedure. After the mannitol infusion
(Fig. 5) the anterior chamber was markedly deep¬
ened. Gonioscopy revealed the angle to be open
(2 plus) in its entire circumference, and on this
basis the referring surgeon elected to do a periph¬
eral iridectomy instead of a filtering procedure. Al¬
though her tension is now controlled on medication,
aqueous outflow is poor. Further surgery may be
necessary.
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Comment.—Since intravenous mannitol
re-formed the anterior chamber in a patient
with malignant glaucoma, we decided to see
if it would deepen the anterior chamber in
this case. Apparently hypertonic mannitol
infusion does decrease the volume of the
posterior segment either by dehydrating the
vitreous or by removing posterior chamber
aqueous. In this case the anterior chamber
deepened, and the iris dropped away from
the trabecular meshwork. Since no periph¬
eral anterior synechias were present, a pe¬
ripheral iridectomy was performed.
Case 7.—This 78-year-old white female requested
treatment because she noticed that the vision in
her right eye had worsened ; previously noted vis¬
ual acuity was only 20/100 in the right eye as a
result of cataractous lens changes. The right eye
was markedly congested, the cornea steamy, and
the angle was closed. Tension of the right eye
was 88 mm. Hg. No miotics or acetazolamide were
administered, but 209?· mannitol infusion was begun.
The tension dropped from 88 mm. Hg to 51 mm.
Hg. A small additional infusion of mannitol was
given without effect, a significant subcutaneous in¬
filtration occurring at this time. Pilocarpine (4%)
drops were then instilled, and 500 mg. of intra¬
venous acetazolamide was given. The tension
dropped to 15 mm. H g (Fig. 6), and a cataract
extraction with complete iridectomy was subse¬
quently performed.
Comment.—Because of this patient's age
and debilitated condition, the intravenous in¬
fusion was given slowly. As a result, the
serum osmolality was not elevated as much
as we would have liked (see Figure), a fact
we should have been able to predict because

of the poor diuretic response. Nonetheless,
a drop of over 35 mm. Hg occurred,
"priming" the eye for a further response to
normotensive levels upon the subsequent ad¬
ministration of miotics and acetazolamide.
We do not recommend that osmotic therapy
should precede standard administration of
miotics and acetazolamide.
Although 15-20 cc. of hypertonic mannitol
infiltrated subcutaneously, there was no ap¬
parent pain, and, next morning, no swelling,
redness, or induration was present at the
infiltrated site. A similar infiltration with
urea could be expected to produce a severe
local reaction.11
Case 8.—This patient had recurrent retinal de¬
tachment. A high scierai buckle was deemed nec¬
essary, but relatively little subretinal fluid was
present. Hypertonic mannitol infusion softened the
eye, and a high buckle was easily effected.
Case 9.—This case is that of a 33-year-old sea¬
man who had severe eye pain for 1 week while at
sea, subsequent to a central retinal vein occlusion
3 months earlier. Because this was a hemorrhagic
glaucoma of 1 week's duration (with 2 plus ante¬
rior chamber flare and cells), the drop in intra¬
ocular pressure from 44 mm. Hg to 29 mm. Hg
was no less than was anticipated. A breakdown
in the blood-aqueous barrier is one reason for the
frequently poor response of hemorrhagic glaucomas
to osmotic therapy. Poor posterior segment circu¬
lation is probably a frequent contributing factor.
Case 10.—A solution of 20% mannitol, 1.1 gm.
per kilogram, was administered to this patient with
central serous retinopathy in an attempt to reduce
posterior pole transudate. The intraocular pressure
was lowered, but the effect on posterior pole fluid
was minimal.
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Fig. 6.—The moderate
response of prolonged
angle-closure glaucoma-
without previous therapy
to 20% mannitol infusion.
Further reduction of the
intraocular pressure to
normotensive levels fol¬
lowed the administration
of pilocarpine drops and
intravenous acetazolam¬
ide.
Comment
Although this is a relatively small series,
there canbe little doubt that intravenous hy¬
pertonic mannitol is an effective osmotic
agent for the reduction of intraocular pres¬
sure. Experience with over fifty neurosurgi-
cal patients has established its safety and
effectiveness in lowering cerebrospinal fluid
pressure (CSF) and decreasing brain mass.12
Ligation of the renal arteries has demon¬
strated the CSF hypotensive effect to be in¬
dependent of the diuretic effect* The
resultant diuresis probably prolongs the hy¬
potensive response. In this regard, water in¬
gestion should probably be somewhat limited,
so that increased serum osmolality levels are
maintained.
A brief comparison of mannitol with urea
is given in Table 2. We have previously used
urea with good results. Its advantages lie in
its low molecular weight and its poor ocular
penetrance. Despite its usefulness it does
have certain disadvantages. Urea is unstable
in solution and must be freshly prepared be¬
fore using, a tedious and time-consuming
chore. It cannot be sterilized by heat. In a
relatively large series of patients 13 84% com¬
plained of severe pain in the arm receiving
the infusion; this has been attributed to the
hypertonicity of the solution but is probably
also related to the proteolytic effect of urea
in 30% solution. Because of this proteolytic
effect, extravasated urea can cause severe
local reaction, and sloughs have occurred.11
 Table 2.—Mannitol and Urea: A Comparison
Local
Formula Mol. Wt. Distribution Dose Solution Activity Reaction Cost

Mannitol CH, OH (CHOH), CH. OH 182 Extracellular fluid 2.0 gm/kg Stable Inert Little Less
UreaNH, CONH. 60 Total body water 1.0 to 1.5 Unstable Proteolytic Marked More
gm/kg

Urea apparently has slight fibrinolytic ac¬ cidental extravasation of hypertonic mannitol
tivity,14 and increased bleeding tendency has seems to provoke considerably less local re¬
been noted in the early stages of neurosurgi- action than does urea (Case 7).
cal operations.15 However, we are not aware There was no evidence of cardiocirculatory
of any reports of severe bleeding related to overload in any of our patients. Larger
urea administration. Experimental evidence dosages given even more rapidly have not
of toxic effect on the heart with marked produced cardiocirculatory overload in over
changes in the electrocardiogram has been 50 neurosurgical patients.12 This is not to say
reported.19 that such overloading cannot occur ; it has
The molecular weight of mannitol is 3 been reported 8—as indeed it has also been
times that of urea. However, mannitol is reported with urea therapy.18
concentrated in the extracellular fluid com¬

partment 16·17 which comprises only one-third Summary

of the total body water (see Table 2) ; the
relative disadvantage of greater molecular
weight is thereby largely overcome. Although
we have not measured the ocular penetrance
of mannitol, we may deduce from our clin¬
ical results that it crosses the blood-aqueous
barrier slowly, if at all.
Mannitol is available in 20% solution for
parenteral infusion. It may require slight
heating for complete solution. We recom¬
mend a dose of 2 gm. per kilogram, infused
over a 30- to 45-minute span. This dose
should be flexible: a smaller dose should be
given if the intraocular pressure is not too
high or if there is cardiocirculatory insuffici¬
ency; a larger dose may be given if the case
is likely to be a refractory one, as in the
presence of marked anterior chamber flare
and cells. Up to 4.25 gm. per kilogram has
been used in neurosurgical patients. A sig¬
nificant diuresis occurred in all of our pa¬
tients except one. Three of our patients were
nauseated, 2 experienced headache, and 2
complained of dizziness ; any osmotic agent
which lowers the intracranial pressure to
negative levels will produce this effect.11 Only
1 of our patients complained of transient arm
pain, suggesting that this symptom will occur
less frequently than with urea infusion. Ac-
Mannitol, the reduced form of mannose, is
stable in solution, easily administered, inert,
and nontoxic. The intravenous administra¬
tion of 20% mannitol solution (2 gm. per
kilogram) has been shown to effectively re¬
duce the intraocular pressure. The concen¬
tration of mannitol in the extracellular fluid
compartment enhances its osmotic efficacy.
Tt is worth remembering that any intra¬
venous infusion, no matter how "inert,"
carries with it some inherent risk. Caution
should be exercised where there is evidence
of cardiocirculatory insufficiency, debility, or
oliguria.
We would like to thank Drs. Frederick C. Cordes,
Michael J. Hogan, George N. Hosford, William
Richardson, and Ariah Schwartz for the privilege of
seeing their patients.
We would also like to thank Drs. Eggert, Fine,
Hales, Morgan, and Reynolds for their assistance.
Robert N. Shaffer, M.D., 490 Post St., San
Francisco, Calif.
Addendum
Since submitting this paper we have used
mannitol in ten additional instances of acute
glaucoma. The results have been uniformly
excellent. Arm pain and phlebitis have not
occurred and other side-effects have been
minimal.

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