Drugs in Perspective

Glycerol: A Review of Its Pharmacology,

Pharmacokinetics, Adverse Reactions, and Clinical Use
Michael S. 6. Frank, M.D., Milap C. Nahata, Pharm.D., and Milo D. Hilty, M.D.

Glycerol is a potent osmotic dehydrating agent with additional effects on brain metabolism. In
doses of 0.25-2.0 g/kg glycerol decreases intracranial pressure in numerous disease states,
including Reye’s syndrome, stroke, encephalitis, meningitis, pseudotumor cerebri, central
nervous system tumor, and space occupying lesions. It is also effective in lowering intraocular
pressure in glaucoma and shrinking the brain during neurosurgical procedures.
Hyperosmolality with rebound cerebral overhydration is of concern, especially in patients with
altered blood brain barriers. They may be avoided if glycerol is administered on an intermittent
rather than a continuous basis. lntravascular hemolysis does not occur with oral use. When
administered intravenously, hemolysis can be minimized by using glycerol 10% in dextrose 5%
with normal saline at rates of 6 mg/kg/min or less. However, intravenous doses of 1-2 g/kg every
2 hr can be administered safely in severe cases of elevated ICP. In such patients, glycerol serum
concentration, serum osmolality and ICP monitoring are required to optimize glycerol therapy.
(Pharmacotherapy 1981;1:147-60)

OUTLINE Introduction
Introduction Glycerol (1,2,3-propanetrioI) is a potent os-
Biochemical Pharmacology motic dehydrating agent that is primarily used
Pharmacokinetics clinically in the treatment of elevated intracranial
Adverse Reactions pressure (ICP). It was first evaluated in animals
Clinical Use in the late 1800’s, but the use of glycerol in man
Reye’s Syndrome was not investigated until 1938.
Comment Glycerol is effective when administered orally
Stroke or intravenously. Oral administration may, how-
Comment ever, be accompanied by nausea and vomiting,
Pseudotumor Cerebri which can be avoided by i.v. use.’, * Intravenous
Comment glycerol may have a more rapid onset of action
Meningitis and Encephalitis than oral glycerol3 and may be more effective in
Comment controlling severe cases of elevated ICP.4’j
Central Nervous System Tumors, Space Despite considerable clinical use, glycerol is
O c c upy ing Lesions, and Neurosurgical not presently commercially manufactured for i.v.
Procedures administration. This is probably because of wide-
Comment spread use of mannitol, which is marketed as an
Central Nervous System Trauma i.v. preparation, and lack of physician familiarity
Comment with the drug. Glycerol, however, offers several
Central Nervous System Asphyxia potential advantages over mannitol. They in-
Comment clude oral administration, less diuresis and asso-
Glaucoma
Comment
Hepatic Coma From the Department of Pediatrics at Columbus Children’s
Diabetes Mellitus Hospital and Ohio State University Colleges of Medicine and
Pharmacy, Columbus.
Comment Address reprint requests to Dr. Milap C. Nahata, College of
Preparation Pharmacy, Ohio State University, 500 West 12th Avenue,
Summary Columbus, OH 43210.

147
148 PHARMACOTHERAPY VOLUME 1, NUMBER
2, S E P T E M B E F ~ ~ C T1981
OBER

Glucose 4
Gluconeogenesis
GI yce raIde hyd e - 3 - phosphate -
GIyco Iys is
Pyr uvate

I Triase phosphate
isomerase

Dihydroxyacetone phosphate

OH OH OH
1 1 1
H-C - C -C-H
Glycerol kinase
*
I
Glycerol -3-
Glycerol - 3 - phosphate
dehydrogenase

phosphate Yw
Triglyceride
I l l Free fatty acid
H H H + ATP
Glycerol

Figure 1. Biochemical pathway for glycerol metabolism.

ciated renal electrolyte loss, and perhaps less re-
bound cerebral overhydration.', ', 5 . 7 In addition
glycerol has a desirable pharmacologic effect on
brain metabolism that is not shared by mannitol.
This effect may enhance the clinical efficacy of
glycerol in stroke and Reye's syndrome pa-
t i e n t ~ . ~Because
,~,~ about 80% of glycerol is
metabolized by the liver, it may be used with a
greater margin of safety than mannitol in pa-
tients with decreased renal function. Since glyc-
erol is a normal intermediary metabolite it can
serve as a source of calories, whereas mannitol
cannot be utilized as a metabolic substrate.'
Biochemical Pharmacology
Glycerol is a naturally occurring trivalent alco-
hol that constitutes the structural core of the tri-
glyceride molecule in man. The normal endoge-
nous fasting serum concentration is about .046
mg/ml.' It has a molecular weight of 92.09. Glyc-
erol is incorporated into intermediate metabo-
lism via two major pathways (Figure 1). After
phosphorylation by glycerol kinase, approxi-
mately 70-90% is oxidized by glycerol-3-phos-
phate dehydrogenase to dihydroxyacetone phos-
phate, which then enters the Embden-Meyerhof
pathway at the level of glyceraldehyde-3-phos-
phate. The remaining 10-30% combines with free
fatty acids to form triglycerides.1°-15 Glycerol
yields 4.32 calories/g when oxidized to carbon
dioxide and water.'
Approximately 80% of glycerol metabolism
occurs in the liver while 10-20% occurs in the
kidney; this distribution corresponds to the pri-
mary locations of glycerol kinase.', ' 6 . l7Glycerol
is filtered and almost completely reabsorbed by
the renal tubules until a serum concentration of
approximately 0.1 5 mg/ml is achieved.18 When
this concentration is exceeded, glycerol appears
in the urine and causes an osmotic diuresis
roughly equivalent to the volume adrninistered.l8-''
Glycerol kinase has been found in small
amounts in intestinal mucosa and brown adipose
In addition, at least some utilization of
g l y ~ e r o l - ~in
~ Cvitro has been demonstrated in
nerve tissue, thyroid, lung, pancreas, mammary
gland, lymphatic tissue, white adipose tissue, leu-
kocytes, spermatozoa, granuloma tissue, and dia-
~ h r a g m . Although
'~ an area of controversy in the
past, several studies have shown that glycerol
enters the brain and cerebral spinal fluid (CSF)
where it can contribute to the oxidative metabo-
lism of the brain.8,24-32
The most potent pharmacologic effect of glyc-
erol is dehydration. It rapidly lowers intraocular
pressure (IOP) and ICP within 10-30 min after an
oral or i.v. dose. The absolute increase in serum
osmolality required to produce significant cere-
bral and intraocular dehydration is not entirely
clear.
The glycerol literature up to the early 1970's
was superbly reviewed by Tourtellotte, et al.'
 GLYCEROL Frank, Nahata, and Hilty
They cited McCurdy, et aI22and stated that “it is
probable that the dosage of glycerol required to
produce ocular dehydration is the same as that
for cerebral dehydration . . . approximately 10
mmole/L (0.9 mg/ml).” However, McCurdy, et al
did not make this statement, and their data
showed effective lowering of ICP within 10-20
min when glycerol serum concentrations were
0.69 mg/ml. Guisado, et a W Z 9implied that in nor-
mal dogs, serum concentrations of 2.7 mg/ml
may be required to effectively shrink the brain
and decrease ICP during a continuous infusion,
while R e i n g l a ~ sshowed
~~ a continuous decline
of ICP in a CNS trauma patient during a 6 hr
infusion when serum glycerol concentrations
never exceeded 0.35 mg/ml. Following oral
doses of glycerol, Rottenberg et a133effectively
lowered ICP in eight subjects in approximately
20 min when the serum osmolality increased by
approximately 7 mOsm/L. These reports and
data on stroke patients discussed below suggest
that the effective lowering of ICP in man may
initially be seen as soon as a serum glycerol con-
centration of 0.45 mg/ml is obtained, and this
may not be entirely due to the simultaneous in-
crease in serum osmolality of approximately 5
mOsm/L.
Studies have shown that glycerol decreases
the sodium and water content of mammalian tis-
sues, especially of cerebral white matter.28,34 Its
effective lowering of ICP has been demonstrated
even in nephrectomized animals,35 suggesting
that it dehydrates the brain by an extrarenal
mechanism.2 It has been shown that glycerol
enters the brain and CSF where it can be used as
a metabolic substrate and improves oxidative
phosphorylation. Glycerol simultaneously in-
creases blood flow to ischemic areas, decreases
serum free fatty acids, and increases synthesis of
glycerides in the brain.7,24-31 Glycerol’s effect on
free fatty acids is particularly interesting in that
free fatty acids alone are capable of producing
coma, increased intracranial pressure, cerebral
edema, and mitochondria1 swelling and dysfunc-
tion in experimental animal^.^, 36-1~ Free fatty
acids or prostaglandins and related compounds
produced from the free fatty acids may be in-
volved in the pathogenesis of edema and mito-
chondrial d y ~ f u n c t i o n .Free
~ ’ fatty acids are also
known to be markedly elevated in the early
stages of Reye’s syndrome where enormous ele-
vations in ICP are seen.42The correction of these
metabolic parameters may thus aid in glycerol’s
effect on lowering ICP, but the main effect still is
derived from its cerebral osmotic dehydrating
action.
In human subjects with relatively intact blood
brain barriers, oral glycerol is generally effective
in lowering ICP for 2-3 hr,33as opposed to the 6
hr previously suggested by Tourtellotte, et a1.2
ICP declines continuously during a constant rate
149
infusion as long as glycerol has not accumulated
in the brain or CSF in high enough concentra-
tions to equalize or reverse the osmotic gradient.
In patients with intact blood brain barriers, the
initial osmotic effect seems to be neutralized
after 4-43 hr of a constant rate infusion when
steady state serum concentrations are achieved.33
In patients with marked alterations in their blood
brain barrier, the gradient is potentially reversed
by this time.28,z9,33.43This “rebound” increase in
ICP may be more related to the preferential pene-
tration of glycerol into CSF, rather than gray or
white matter, with resultant alterations in CSF
dynamics.28,29.33
Even if glycerol fails to enter the brain and CSF
in appreciable amounts to cause an influx of
water, brain osmolality will eventually rise simply
i n response t o a c h r o n i c a l l y hyperosmotic
serum. This is achieved by increasing intracellu-
lar sodium and/or idiogenic osmos, probably
amino
Other pharmacologic effects that have been
observed in animals and have no clear clinical
relevance include increased i r r i t a b i l i t y of
muscles, relaxation of the gallbladder sphincter,
and increased force and amplitude of intestinal
contraction^.^^ Glycerol has been employed satis-
factorily as a partial dietary substitute for carbo-
hydrate over an extended period of time,46 be-
cause it is a substrate for gluconeogenesis. The
diuresis with glycerol is usually not accompa-
nied by as prominent an electrolyte loss as seen
with mannitol, whose elimination depends solely
upon renal excretion.’, 5 , 22
Pharmacokinetics
Limited pharmacokinetic data are available on
glycerol. When given orally to humans, it is well
absorbed and peak serum concentrations occur
at 60-90 min.33 McCurdy, et reported a
plasma concentration of about 1.45 mg/ml at 60-
90 min after a single 1-1.27 g/kg oral dose of
glycerol. Senior, et a147 administered glycerol
0.25 g/kg (estimated from 120 mM/m2) i.v. over 4
minutes and found a peak plasma concentration
of 0.9 mg/ml. R e i n g l a s ~
reported
~~ a plasma con-
centration of 0.34 mg/ml at the termination of a 6
hr constant rate infusion of 1.5 g/kg i.v. glycerol.
I n patients with Reye’s syndrome, we have
observed a large variation in steady state glyc-
erol serum concentration^.^^ Glycerol infusions
ranging from 0.38-0.88 g/kg/hr attained serum
concentrations of 1.48-5.83 mg/ml. Snyder, et
a149reported glycerol steady state serum concen-
trations of 0.8-7.0 mg/ml in 10 patients with nor-
mal hepatic and renal function following con-
stant i.v. infusion of 0.14.87 g/kg/hr.
Previous investigators have suggested that the
distribution of glycerol corresponds to the extra-
cellular space, which is 50-65O/0 of the body
150 PHARMACOTHERAPY VOLUME 1, NUMBER
weight, but the method of their calculation was
not ~ l e a r . lGlycerol
~ , ~ ~ is known to rapidly enter
red blood cells,’ and it is felt that intravascular
glycerol probably equilibrates with the tissue
water within minutes during a continuous infu-
sion at a constant The degree of protein
binding of glycerol has not to our knowledge
been investigated.
As previously mentioned, renal tubular reab-
sorption of the filtered glycerol load is practically
complete at serum levels less than 0.15 mg/ml.18
During continuous infusions of large doses, up
to 55% of the administered dose may appear
unchanged in the urine.lg
The elimination half life of glycerol in man is
about 30-45 r n i n . ’ ~In~ ~our Reye’s syndrome
patients, total body clearance of glycerol has
ranged from 1.94-5.1 r n l / k g / r n i r ~ .This
~ ~ com-
pares well with the mean clearance of 2.17
ml/kg/min reported by Snyder, et a149 in 10
patients with normal liver function. Since glyc-
erol is largely metabolized by the liver, and liver
function is profoundly disturbed in Reye’s syn-
d r o m e patients, g l y c e r o l clearance may be
higher in other disease states where liver func-
tion is normal. Snyder, et a149reported a patient
with head trauma and normal liver function as
having almost twice the clearance of glycerol as
a patient with Reye’s syndrome. However, they
observed a comparable variation in clearance in
adults without significant liver dysfunction.
I n all human studies, glycerol clearances were
substantially lower than normal liver blood flow,
1.5 L/min, suggesting that glycerol may not
undergo a significant first-pass effect. This is
consistent with the findings (based on conver-
sion of animal data to man) that similar oral and
intravenous glycerol doses would be required to
produce the same effect on cerebral edema.’, 23
Based on limited data in Reye’s syndrome, it
appears that glycerol clearance is constant over
a dose range of 0.38-0.88 g/kg/hr. This is in con-
flict with the saturable process reported in dogs
at a glycerol dose of 0.32 g/kg/hr.23
A two- to-threefold intersubject variation in
total body clearance of glycerol explains, in part,
?he need for the large range of doses required to
control ICP in Reye’s syndrome. Further studies
are indicated in Reye’s syndrome and other dis-
eases to develop specific dosing guidelines.
Until such data are available, serum concentra-
tions of glycerol may be monitored in patients
with serious illness to maximize therapeutic bene-
fit and minimize dose-related hemolysis and
renal toxicity. In institutions where a glycerol
assay is not available, close monitoring of serum
osmolality is a reasonable alternative.
Adverse Reactions
Notable adverse reactions of glycerol in man
i n c l u d e intravascular hemolysis, hemoglobi-
2, SEPTEMBER/~CTOBER
1981
nuria, renal damage, hyperglycemia, and hyper-
osmolality. Single 8-15 g/kg doses in animals
produced restlessness and diminished activity
followed by an increasing pulse rate, vomiting,
occasional biting movements, cyanosis, tremor,
diuresis, some loss in equilibrium, severe clonic
convulsions, and even death.45However, in man
this sequence has never been observed; a child
ingested 300 g and went into coma but ultimately
recovered ~ o m p l e t e l y .One
~ ~ fatality has been
reported in the German literature, but the dose
and mode of administration were not known.45
Rare fatal reports in the literature seem to have
followed irreversible renal damage, but the
causal relationship to glycerol outlined below is
difficult to establish.
Tourtellotte, et at2 extensively reviewed the
early literature on intravascular hemolysis due to
glycerol and concluded that glycerol adminis-
tered, even in small amounts intraperitoneally or
subcutaneously, consistently produced hemoglo-
binuria, while hemolysis from i.v. administration
depended upon the tonicity of the glycerol-
saline solution. Glycerol was known to rapidly
enter the cells and cause fluid influx, swelling
and hemolysis,2 but this was prevented in vitro if
at least 0.45% saline was used with concentra-
tions of glycerol up to as high as 50%. Deich-
man4’ and Cameron, et also produced hemoglo-
binuria in rats with 50% glycerol i.v., while no
hemolysis was seen with 20% glycerol i.v. at a
dose of 4 g/kg. Zilversmit, et all8 used 10% glyc-
erol in normal saline and reported no hemolysis
in doses of up to 4-8 g/day. Their review found
no reports of hemoglobinuria when glycerol was
administered orally in doses of 9 g/kg/day for
one year in dogs or 2.2 g/kg/day for 50 days in
college
The adverse effects of i.v. glycerol’, 3. 5 , 6, 13, 24, 30,
32. 35, 43. 47, 48, 51+1 are summarized in Table 1. The
cited studies have concentrated on the impor-
tance of rate of i.v. administration, but because
of variation in glycerol-saline concentration, the
relationship between rate of administration and
the degree and significance of hemolysis re-
mains to be delineated. It would appear, how-
ever, that hemolysis can be greatly minimized if
glycerol 5-10% is administered in dextrose 5%
with normal saline at a rate equal to or less than 6
mg/kg/min, but rates as high as 33 mg/kg/min
have been administered safely for several days.
A l t h o u g h hemolysis and h e m o g l o b i n u r i a
caused by i.v. glycerol can produce renal dam-
age, subcutaneous glycerol has also been associ-
ated with renal damage in rats. This toxicity,
apparently not attributable to myoglobin, can be
prevented by excision of the infiltrated tissue in
less than two minutes, suggesting that some
renal toxin may be p r ~ d u c e d . ~ O T h
toxin
e has not
been isolated, however. Renal biopsy studies by
Oken, et aI6’ and Hobbs, et aP3 suggested that a
 GLYCEROL Frank, Nahata, and Hilty 151

Table 1. Adverse Reactions to Intravenous Glycerol

Solution
OO
/ Glycerol/
Disease / Dextrose/
OO Adverse Reactions
(Number of O/O Sodium Dose, interval, Rate (Number of
Authors Patients) Chloride duration (mg/kg/min) Patients)
Cantore, et all Neurosu rg icala(258) 30/10/0.9 0.8--1 g/kg over 4.2b Frequent hemoglo-
4 hr for 1 dose binuria
Meyer, et ,I3 Stroke (17) 1o/-/0.9 0.8 g/kg over 8-1 0.6 None
75-100 min
for 1 dose
Mickell. et at5 Reye’s (12) 10/5/0.25 0.5 g/kg over 5.6-1 6 Gross hemolysis (3)
CNS Trauma (12) 30 min, then Hemoglobinuria (25)
Asphyxia (5) 0.5 g/kg over t Osmolality (1)
Encephalitis (4) 90 min, repeated
Meningitis (1) every 2 hr for un-
CNS Tumor (4) specified days
Cook. et ,I6 Reye’s (25) 10/5/-‘ 0.5 g/kg over 5.6-1 6 Hypernatremia (2)
30 min, then 0.5 g/kg Serum osmolality
over 90 min re- as high as 358
peated every 2 hr mOsm/L
for unspecified days
Wolf, et all3 Newborn (21) 2/-/0.9 0.1 g/kg over 20 None
5 min for 1 dose
Sloviter, et aIz4 Various malig- 5/-/0.9 1.2-2 g/kg over 3.1- 1 None
nancies (12) 3.5-6 hr for 1 dose
Meyer, et aI3O Stroke (9) lo/-/0.9 1.2 g/kg over .83 None
24 hr for 4 days
Reinglass3’ CNS Trauma (1) lo/-/0.45 1.5 g/kg over 4.1 None
6 hr for 1 dose
Bovet. et a135 CNS Tumor (12) 30/6/0.gd 0.8-1 g/kg 1.6!jb Minimal hemolysis
CNS Abscess (1) if i.v. rate < 70
CNS Trauma (2) drops/min.e
Guisado, et a143 CNS Tumor (1) 1o/-/0.9 1.3g/kg over 2.6-12.6 I osmolality and
8 hr for 24 hr “rebound”
then 2.6 g/kg
over 8 hr
Senior, et aI4’ Controls (21) lo/-/0.9 0.25 g/kg 62.5 None
over 4 minf
Nahata, et aI4* Reye’s (9) 10/5/0.45 0.75-1.75 g/kg 4-29 Hemolysis (1)
every 2 hr for t Creatinine (1)
1-4 days
Fawer, et aI5’ Stroke (26) 10/5/0.9 25 g every 12 hr 2.gb None
over 2 hr for
6 days
Frithz, et aF2 Stroke (50) 10/5/0.25 50 g over 6 hr 2b None
every day for 6 days
Gilsanz, et a153 Stroke (30) 1o/-/0.9 50 g over 24 hr 0.5b Hernoglobinuria
for 6 days and death from
renal failure (1)
Thrombophle-
bitis (3)
Hagnevik, et a154 CNS Tumor (3) 20/-/0.9 1 g/kg over 15-60 17-67 Hemolysis (3)
min for 1 dose 1 renal function
(11
Kerzner, et als5 Reye’s (19) 10/5/0.454.9 1-2 g/kg every 3.3-8.3 I osmolality (4)
2 hr for 4-1 0 days
152 PHARMACOTHERAPY VOLUME1, NUMBER2, SEPTEMBER/~CTOBER
1981

Table 1. Adverse Reactions to Intravenous Glycerol (continued)

Solution
OO
/ Glycerol/
Disease YO Dextrose/ Adverse Reactions
(Number of / Sodium
OO Dose, interval, Rate (Number of
Authors Patients) Chloride duration (mg/kg/min) Patients)

Krausz, et a156 Stroke (1) 1o/-/0.9 50 g over 20 min 35.7b Renocerebral

for 1 dose oxalosis
Larsson, et aI5’ Stroke (12) 10/5/- 50 g over 6 hr 2.0b None
for 6 days
Phadke, et a158 Meningitis (11) lo/-/0.9 35 g over 2 hr 4.16b None
Stroke (12) for 1 dose
Hypertension (8)
SOL (4)9
Record, et a159 Hepatic coma (5) lo/-/- 50 g over 24 hr 0.5b None
Control (1) for 1 dose 4.6-7b Slight hernolysis
6.5 g bolus
then 13 g over
40 min
Virno60 Glaucoma (16) 30/20% So- 0.6 g/kg over 30-40 None
dium ascor- 15-20 min
bate for 1 dose
WelchG1 Stroke (500) 1o/-/0.9 50 g over 6 hr 2b Hemolysis only if
every day for rate t to 7-14 mg/
7-10 days kg/min
alntravenous glycerol used in only a limited, unspecified number of these patients.
bEstirnated rate using 70 kg as average weight when not specified by author.
CPotassium phosphate (2 mg/100 cm) added to solution.
dBest results with this solution - 6% Dextran used instead of Dextrose.
eMl/min not specified.
fEstirnated from 120 rnrnoles/m* dose.
%pace occupying lesion.

decreasing renal tubular flow rate was the precip-
itating event, and that renal damage could be pre-
vented by increasing glomerular flow rates with
the i.v. administration of mannitol or sodium
ascorbate. Krauz, et a156reported one case of pro-
posed renocerebral oxalosis following i.v. 10%
glycerol in a patient with a massive stroke. The
patient died within 5 hr of admission and had
multiple complicating factors, making this report
difficult to interpret.
Other important toxicities include hyperglyce-
mia and hyperosmolarity. Since glycerol is incor-
porated into the Embden-Meyerhof pathway,
serum glucose concentration is increased.l5.47
This has rarely been a clinical problem, except in
patients with diabetes.l0.64 Transient hepatomeg-
aly due to glycogen storage may occur, but this
is reversible after cessation of administration.
Glycerol substantially increases serum osmo-
lality and when used continuously it may cause a
profound hyperosmotic state, especially in the
diabetic ~ a t i e n t .At
~ the
, ~ ~present time some cen-
ters are using glycerol on a continuous basis and
achieving sustained serum osmolalities greater
than 340 mOsm/L over the several days required
to treat severe cases of elevated ICP. Glycerol is
then tapered over the same period of time to
avoid rebound cerebral overhydration. In our 30
patients with Reye’s syndrome receiving i.v.
glycerol 1-2 g/kg according to the regimen of
Mickell et al,5 an increase in serum osmolality
(350-400 mOsm/L) was observed in all patients.
This necessitates careful monitoring of serum
osmolality in all patients receiving the drug for
prolonged periods of time, especially in those
with a marked breakdown of the blood brain bar-
rier. Whether or not protracted elevation in
serum osmolality alone may result in long-term
neurologic problems remains to be elucidated.
However, the short term benefits of glycerol in
controlling ICP and decreasing mortality have
been impressive, especially in patients with
Reye’s
Clinical Use
Oral and intravenous glycerol have been used
in a number of clinical situations, including: ele-
p h a n t i as i s,G5g I a u c o m a, 6 0 , 66-73 pseud ot u m o r
I
 GLYCEROL frank, Nahata, and Hilty
cerebri,’, 2,74-78 CNS trauma,’, 5 , 32s 79 CNS tumors
and space o c c u p y i n g lesion s,’, 5 . 33, 3 5 . 4 3 , 5 8 , 8o
hypertensive e n ~ e p h a l o p a t h y stroke,’, ,~~ 3 , 8 , 30.
51, 53. 57, 58. 61,81 e n ~ e p h a l i t i sbacterial,
,~~ aseptic and
tuberculous 58, 76.82 diabetes melli-
tus,,, 5 , lo, 64 brain a ~ p h y x i a ,hepatic ~ coma,59
Reye’s s y n d r ~ m e , ~55, ~and . ~ ,during neurosurgi-
cal procedures.’, 5 , 35, 57 Throughout this review,
specific reference to measurements of ICP (1
mm CSF = 1 mm H,O = 0.075 mm Hg) will be
made; normal values are less than 200 mm CSF
or H,O and less than 15 mm Hg.
Reye’s syndrome
Mickell, et a15 studied 12 patients with Reye’s
syndrome in a series of 42 patients with in-
creased ICP of various etiologies. They adminis-
tered 10% glycerol in dextrose 5% with sodium
chloride 0.25% in i.v. doses up to 1 g/kg every 2
hr. For most children with moderate to severe
intracranial hypertension, best results were ob-
tained with an every 2 hr infusion of 1 g/kg, giv-
ing the first 0.5 g/kg over 30 rnin and the second
0.5 g/kg over the next 90 min. The precise ther-
apy in the 12 Reye’s patients was not specified,
and effectiveness was not subjected to statistical
analysis.
Shaywitz, et a14used oral glycerol in 2 patients
in 1 g/kg doses every 2-3 hr by nasogastric (NG)
tube and observed a lowering of ICP in 3 0 4 0
min. However, the lowering lasted only a short
time and thus was felt to be relatively ineffective.
Cook, et aI6 administered 10% glycerol in dex-
trose 5% with potassium phosphate 0.002% in
doses of 1 g/kg every 2 hr in 25 patients with
Reye’s syndrome; the first half was given over 30
rnin and the next half over 90 min. Specific data
on each patient were not supplied, but it was sug-
gested that glycerol was more effective than man-
nitol in controlling ICP.
Kerzner, et a155reported a series of 19 Reye’s
syndrome patients who were given intravenous
glycerol in low (0.2-0.5 g/kg/hr) or high (greater
than 0.5 g/kg/hr) doses. He showed a better ther-
apeutic outcome in the high dose group.
We have successfully treated an additional 30
Reye’s syndrome patients at Children’s Hospital,
Columbus, with intravenous glycerol 1-2 g/kg
given according to the schedule proposed by
Mickell, et al.5 Eleven patients were in stage 1-11
coma and 19 in stage Ill or deeper coma. The
latter group had continuous ICP monitoring dur-
ing therapy.
Comment
Intravenous glycerol effectively lowers ICP in
patients with Reye’s syndrome, while oral glyc-
erol has a limited role in this condition. MickelP
recommends 10% glycerol in isotonic saline
given over 30 rnin as an alternative to mannitol;
153
he gives a dose of 0.25-1 g/kg i.v. during acute
elevations of ICP greater than 30 mm Hg that are
unresponsive to bag ventilation. He also recom-
mends maintaining serum osmolarity at less than
340 mOsm/L and preferably at less than 320
mOsm/L.
In mild to moderate intracranial hypertension
i.v. boluses of 0.5-1 .O g/kg over 30 rnin every 2-4
hr are satisfactory. In more severely ill patients
ICP can be maintained at less than 15 mm Hg
with 1-2 g/kg every 2 hr by constant infusion;
half of the dose should be given over 30 min and
the second half over the next 90 min. Every 2 hr
infusions of doses as high as 2.0 g/kg have been
given safely at our institution without significant
toxicity. The optimal dosage schedule for each
patient must be individualized, and ICP monitor-
ing is essential for proper management.
Theoretically, bolus dosage is preferable to
constant infusion because it will minimize glyc-
erol’s penetration into the brain, limit the degree
of rebound cerebral edema, and prevent exces-
sive or prolonged elevation of serum osmolarity.
Combined intensive supportive care and glyc-
erol osmotherapy has improved survival of pa-
tients with Reye’s syndrome at our institution.
The relative value of mannitol versus glycerol for
osmotherapy in Reye’s syndrome is not clear and
should be critically evaluated. The most impor-
tant factors in successful management of pa-
tients with Reye’s syndrome include aggressive
supportive care with intracranial pressure moni-
toring and constant attendance of experienced
medical staff.
Stroke
Glycerol was first used by Cantore, et all i n 12
patients with stroke among 258 neurosurgical
patients. Although no specific data were pre-
sented for the stroke patients, oral doses of 1.5
g/kg followed by 0.5-0.7 g/kg every 3 hr de-
creased ICP within 3 0 4 0 min, and the effect
lasted 2-3 hr.
Meyer, et aVOtreated 36 patients within 72 hr of
onset of symptoms with either 10% glycerol in
dextrose 5% with normal saline or 50% oral glyc-
erol solution in orange or lemon juice. Glycerol
doses were 1.2 g/kg/day given by i.v. continuous
infusion over 24 hr, or 1.5 g/kg/day given in 6
oral doses. Survival rate was 8l%, and neuro-
l o g i c improvement a n d a decrease i n ICP
occurred during and at the end of 4 days of treat-
ment with no significant toxicity. Further studies
by Meyers, et a13,8,31 involved a series of 17, 22,
and 54 stroke patients, including 12 with diabe-
tes. They observed redistribution of blood flow to
ischemic areas, improvement of mitochondria1
oxidative phosphorylation, and clinical and elec-
troencephalographic improvement.
Frithz, et a152showed neurologic improvement
154 PHARMACOTHERAPY VOLUME 1, NUMBER
and no toxicity in 50 patients given 50 g of glyc-
erol in a 10% solution in dextrose 5% with sodium
chloride 0.2% over 6 hr each day for 6 days. In 30
patients treated with 10% glycerol in normal
saline in doses of 50 g over 24 hr for 6 days,
Gilsanz, et showed better neurologic out-
come compared to a dexamethasone-treated
group. One patient died with hemoglobinuria
and renal failure. Phadke, et als8reported on 12
stroke patients among 35 patients treated with
10% glycerol in normal saline at a dose of 35 g
over 2 hr for one dose. They noted a mean reduc-
tion in ICP of 41.8 mm CSF after one hr and 23.6
mm CSF in 24 hr but provided no other specific
data.
Larsson, et aF7 demonstrated no difference in
mortality or neurologic outcome in a double-
blind series of 27 stroke patients treated within 6
hr of onset of symptoms. They were given either
5% dextrose or 10% glycerol in dextrose 5% at a
rate of 500 ml over 6 hr daily for 6 days. Another
controlled study by Fawer, et aIs1evaluated 26 of
51 stroke patients treated with 10% glycerol in
dextrose 5% with normal saline in doses of 25 g
over 2 hr every 12 hr for 6 days. They reported no
decrease in mortality and a statistically signifi-
cant but transient improvement in global perform-
ance and motor sensory functions in patients
with moderate disability.
Comment
The report of the Joint Committee for Stroke
Resources Study Group on Brain Edema in
Stroke81 concluded that I'.. . the clinical hemo-
dynamic and metabolic results, taken together
suggest that glycerol has a beneficial metabolic
as well as hyperosmolar effect on ischemic brain,
improving oxidative metabolism and lipid synthe-
sis . . . In patients with brain edema, glycerol
reduces ICP as well as dehydrates normal brain
tissue by its hyperosmolar action, and of all avail-
able hyperosmolar agents, shows the least equi-
librium concentration in the brain with little or no
rebound rise in intracranial pressure . . ." The
report suggests that glycerol be administered
orally in doses of 1.5 g/kg/day, divided into 6
parts or given i.v. in a dose of 1.2 g/kg/day in 5%
dextrose with normal saline. If given i.v., the dose
should not exceed 500 ml over a 4 hr interval to
avoid hemolysis. These recommended daily
doses may be conservative, and this could ex-
plain the lack of significant improvement in the
more recent controlled clinical trials.
Pseudot u mor Cere bri
Cantore, et all included two patients with pseu-
dotumor in their 258 neurosurgical patients. He
administered 50% glycerol orally in an initial
dose of 1.5 g/kg followed by 0 . 5 4 . 7 g/kg every 3
hr and noted a decrease in ICP within 30-60 min.
2, SEPTEMBER/~CTOBER
1981
Buckell, et a174treated 2 patients with 50% glyc-
erol in lemon juice in doses of 75 g sipped slowly
over 20 rnin 1,2, or 3 times a day as needed. In a
control patient who was given a dose of 0.66 g/kg
they observed a rise in serum osmolality of about
25 mOsm/L, which peaked at about 100 min.
They also noted a transient increase in urine flow
from 1.5 to 4 ml/min over an hour, but this re-
turned to baseline by about 3 hr in the control
patient. In the 2 pseudotumor patients, ICP de-
creased within 10 min with an absolute fall from
350 mm CSF to 90 mm CSF in 115 rnin in one
patient and 330 mm CSF to 150 m m CSF in 60
min in the other patient.
A b s ~ l o n treated
'~ one patient with 1 g/kg orally
three times a day for 18 weeks and noticed a
decrease in papilledema, which, however, in-
creased when glycerol was stopped for 3 days.
Newkirk' treated one patient with 0.5 g/kg
orally every 6 hr for 15 days with complete resolu-
tion of symptoms. The initial ICP drop with the
first dose was 240 mm CSF to 120 mm CSF over 1
hr. A second patient received 1.5 g/kg orally with
a decrease in ICP from 400 mm CSF to 150 mm
CSF within 15 rnin and to 100 mm CSF by 1 hr.
However, glycerol had to be discontinued be-
cause of nausea and vomiting.
Mathew, et a177treated 2 patients with glycerol
0.5 g/kg orally 3 times a day for 6 months. I n one
case, the initial ICP was 380 mm CSF, which sub-
sequently declined to 240 mm CSF after removal
of CSF during lumbar puncture. After 6 months
of glycerol therapy the pressure was 230 mm
CSF. Headaches were absent after 2 weeks, and
papilledema resolved after 18 weeks of treat-
ment. The second case showed an initial ICP of
375 mm CSF, which was lowered to 260 mm CSF
after removal of CSF during lumbar puncture.
After 4% months of glycerol 0.5 g/kg 3 times
daily, ICP was 290 mm CSF. Headache resolved
by 3 months, and no toxicity was observed. Jef-
ferson, et a178treated 7 patients with oral glycerol
1-1.5 g/kg/day and noted improvement of the
blind spot in as little as 6 weeks in one patient.
Comment
Oral glycerol, 0.25-1.0 g/kg given 3-6 times
daily, seems effective in lowering ICP associated
with pseudotumor cerebri. It has been shown to
effectively decrease headaches and papilledema
and to improve the blind spot. Because of the
need to use the agent for prolonged periods of
time, the oral route is preferable to i.v. administra-
tion. At the doses tested, toxicity other than
some nausea has not been reported, even when
the drug was used continuously for up to 6
months.
Meningitis and Encephalitis
Newkirk, et a17Streated a 19-year-old patient
 GLYCEROL Frank, Nahata, and Hilty
with viral meningoencephalitis with 0.5 g/kg of
oral glycerol every 6 hr for 3 weeks, starting on
day 25 of the illness. ICP was reduced from 400
mm CSF to 300 mm CSF within 15 min after the
first dose. Five hours later, the CSF pressure was
up to 330 mm CSF; it then fell to 240 mm CSF
within 15 min of another oral dose. The patient
was treated for 3 weeks and his last CSF pres-
sure was 186 mm CSF 16 hr after the last dose.
Progressive neurologic recovery was noted, and
no complications of therapy were observed.
Mickell, et a15 treated 2 patients with encephali-
tis and 2 with postinfectious encephalopathy
with their dosing method as described before.
The specific complication of hemoglobinuria
found in 25 of their 41 patients was not stated in
these four cases. A normal recovery was seen in
3 patients, and an expressive aphasia was noted
in the fourth.
Phadke, et a15*treated 8 patients with tubercu-
lous meningitis and 2 with pyogenic meningitis
with a single i.v. 35 g dose of glycerol given as a
10% solution in normal saline over 2 hr. They
reported a mean reduction in ICP of 53.7 mm
CSF and 31.25 mm CSF after 1 hr and 24 hr
respectively in patients with tuberculous meningi-
tis and 60 mm CSF and 20 mm CSF in patients
with pyogenic infection. Maximum reduction of
ICP was seen in the tuberculous group (100 mm
CSF in one patient), and all of these patients had
marked improvement of neurologic status. They
reported no significant toxicity with glycerol.
Herson, et a182 reported the use of glycerol 1.5
g/kg every 4 hr by nasogastric tube in 3 patients
with bacterial meningitis. All patients survived
without major complications despite poor prog-
nostic signs on admission.
Comment
Oral and i.v. glycerol have been effective in rap-
idly lowering elevated ICP associated with menin-
gitis and meningoencephalitis. Because of the
breakdown in the blood brain barrier associated
with these diseases, glycerol probably should be
used on an intermittent basis to avoid apprecia-
ble accumulation in the brain. From the above
studies a dose of 0.5-1 .O g/kg given every 4-6 hr
seems reasonable. Initially, glycerol can be used
i.v. over 30-60 min and then orally if prolonged
therapy is required. Careful monitoring of ICP
may help avoid a rebound increase in ICP, espe-
cially if the dose is given more frequently than
every 4 hr.
Central Nervous System Tumors, Space
Occupying Lesions, and Neurosurgical
Procedures
Bovet, et a135described the first large scale clin-
ical use of glycerol in 112 neurosurgical patients,
155
68 of whom had central nervous system (CNS)
tumors or space occupying lesions (SOL). They
administered 3 0 5 0 % oral solutions in doses of
0.5-2.0 g/kg, generally beginning with 1 g/kg fol-
lowed by 0.5 g/kg every 3 hr; results with this
dosage were termed “good.” In 12 patients they
administered 30% glycerol in 6% dextran with
normal saline in doses of 0.8-1 .O g/kg at rates of
10 drops/min or less (mg/kg/min not specified);
results were “good to modest.” Cantore, et all
treated 62 patients with SOL before surgery with
various doses of oral glycerol. Stuporous pa-
tients received 0.5 g/kg every 3-4 hr and experi-
enced marked neurologic improvement within
30-60 min. Glycerol 1.5-2.0 g/kg was given by
nasogastric tube to 75 patients during intra-
cranial surgery, and evidence of significant re-
duction in brain volume was found within 40-60
min. The brain gradually retracted, thus facilitat-
ing operative procedures. Oral glycerol was also
effective in treating 84 postoperative patients
with signs of cerebral edema as well as 25 pa-
tients with post-irradiation cerebral edema.
Guisado, et a143alerted the medical community
to the potential of rebound increase in ICP after
continuous infusion of glycerol. In a patient with
gliobastoma multiforme, they administered 10%
glycerol in normal saline at an initial rate of 2.6
mg/kg/min, which maintained an increase in
serum osmolality of 15 mOsm/L and a glycerol
serum concentration of 0.48 mg/ml. During the 8
hour infusion ICP decreased from 400 mm H,O
to 200 mm H,O. However, after 24 hr of infusion
the ICP continued to rise, despite increases in
the rate of infusion. The patient eventually died,
and the authors concluded that a marked break-
down in the blood brain barrier was responsible
for the severe “rebound” complication.
Mickell, et a15 did not mention the specific
doses of glycerol used in 2 of the 4 patients with
CNS tumors. KuglerB0looked at ICP in 2 patients
with aqueductal stenosis following 1 g/kg dose
from oral glycerol. He documented a decline in
ICP of 200 mm H,O to 70 mm H,O within 30 min,
which persisted for 2 hr and then rose back to
pretreatment levels by 6 hr.
Phadke, et a158treated 4 patients with SOL with
10% glycerol in normal saline with one dose of 35
g given i.v. over 120 min. ICP reductions at 1 and
24 hr of 40 mm CSF and 32.5 mm CSF were
noted, and no complications were observed.
Rottenberg, et treated 6 patients with
meningeal carcinoma and 2 with acute lympho-
cytic leukemia with oral doses of 0.5-1.5 g/kg.
They showed a prompt decrease in ICP within 30
min in 7 of 8 patients; this lasted 150-250 min and
was associated with an average increase in
serum osmolarity of 10 mOsm/L. By 4 5 hr there
was no significant difference between CSF and
plasma osmolality. Three days of oral glycerol
given every 6 hr did not diminish the ICP lower-
156 PHARMACOTHERAPY VOLUME 1, NUMBER
ing effect of a single oral dose of 1 g/kg but when
given to one patient on an every 4 hr schedule
basis, a reverse osmotic gradient was produced,
which resulted in rebound cerebral overhydra-
tion.
Comment
Oral and intravenous glycerol have been used
successfully in the treatment of ICP associated
with CNS tumor, SOL and neurosurgical proce-
dures. One time pre-op doses of 1.5-2.0 g/kg
through a nasogastric tube 30 min prior to inci-
sion of the dura produces significant reduction
in brain volume, which lasts several hours.
Recent data indicate that i.v. doses of 1 g/kg over
30 min provide similar results. For more pro-
longed control of elevated ICP 1 g/kg doses can
be given every 6 hr orally or i.v. over 30-60 min
for the first several days. If required more fre-
quently than every 6 hr, glycerol may penetrate
the CSF to reverse the osmotic gradient and
result in rebound overhydration of the brain. This
is of special concern in patients with marked
alterations of the blood brain barrier.
Central Nervous System Trauma
Bovet, et aP5 used oral glycerol 1 g/kg preoper-
atively in 10 of 12 patients with CNS trauma. Nine
had “good or modest” neurologic improvement.
Two patients received a postoperative i.v. dose of
0.8-1 .O g/kg of glycerol as a 30% solution in 6%
dextran with normal saline, which resulted in
“poor to modest” benefits. Cantore, et all treated
25 CNS trauma patients for several days using
daily oral doses of glycerol 1.0-2.0 g/kg after
intracranial hematomas had been excluded by
diagnostic studies. He did not report specific neu-
rologic improvement in these cases.
In 3 patients with “severe brain injury” Troup,
et a179 showed a significant lowering of ICP
within 1 hr after 2 5 5 0 g of oral glycerol. One
patient had a marked rebound increase in ICP,
which was probably related to an accumulation
of blood from an intracerebral hematoma. In 12
CNS trauma patients with extremely elevated
ICP, Mickell, et a15 used i.v. glycerol successfully
in doses described previously.
Reingla~s3~ reported the results of a 6 hr contin-
uous infusion of 10% glycerol in half normal
saline at a dose of 1.5 g/kg in a patient who had
CNS trauma and was stabilized on a ventilator.
Serum glycerol concentrations gradually in-
creased to 0.35 mg/ml, with a resultant increase
in serum osmolality of 20 mOsm/L. ICP dropped
continuously from 260 mm H,O to 100 mm H,O
over the 6 hr and remained below preinfusion
levels for an additional 6 hr. There was no toxic-
ity or marked diuresis, nor was any neurologic
improvement noted. He suggested that because
of the markedly intact blood brain barrier in this
2, S E P T E M B E ~ ~ C T1981
OBER
patient, similar patients might best be treated
with such a semicontinuous infusion dose for an
anticipated antiedema effect lasting 15-24 hr
before requiring another 6 hr infusion. The only
problem with his data is that an increase of 20
mOsm/L in serum osmolality cannot be ac-
counted for by the serum glycerol concentration
achieved.
Comment
Glycerol has been used effectively in the treat-
ment of cerebral edema secondary to CNS
trauma. Immediate control can be obtained with
total oral doses as small as 2 5 5 0 g, while oral
doses of 0.25-0.5 g/kg every 4-6 hr can be used
for prolonged therapy. Initial i.v. doses of 0.5-1 .O
g/kg over 30 min can be equally successful in
early acute care. Intravenous doses of 1 g/kg
every 2 hr via constant infusion with varying
rates can be effective in more severe cases, while
one daily 6 hr infusion of 1.5 g/kg may be all that
is required in patients with markedly intact blood
brain barriers.
Central Nervous System Asphyxia
Mickell, et a15 studied four drowning patients
and one with a foreign body aspiration. At glyc-
erol doses discussed previously, three experi-
enced hyperglycemia, two hypernatremia, and
one hyperosmolality greater than 340 mOsm/L.
Eventually, three patients died, one remained in
coma, and another experienced impaired con-
sciousness.
Comment
Limited data suggest the need to individualize
glycerol therapy, especially in those patients
with marked breakdown of the blood brain bar-
rier. Vigorous control of ICP may be needed for
prolonged periods of time. With continued use of
glycerol, more of the drug accumulates in the
brain, and more is required to recreate an
osmotic gradient. This sets up a vicious cycle
with potential complications of hyperglycemia,
hypernatremia, or hyperosmolarity. Those pa-
tients who are presently being treated with other
modalities, including hypothermia and barbitu-
rate coma, will likely benefit from osmotherapy
as long as it is not overused. The optimal dosing
schedule is unclear, but as mentioned in the sec-
t i o n o n Reye’s syndrome, intermittent (as
needed) administration may be preferable to
avoid complications.
Glaucoma
Since the 1960’s numerous reports of glycerol
efficacy i n glaucoma have been published.
Trevor-Roper72 suggested that oral doses of 1.5
g/kg can “promptly soften normal eyes and those
 GLYCEROL Frank, Nahata, and Hilty
congested from glaucoma and keep them soft for
about 5 hours.” Consul, et aP8 found oral doses
of 1.O-1.5 g/kg effective in lowering intraocular
tension in 15 normal subjects and 32 cases of
acute, chronic wide-angle, and aphakic glau-
coma. Pressure reduction was noticeable within
30 rnin and decreased to normal values within
1-2 hr. McCurdy, et aIz2studied 8 normal sub-
jects and showed a decline in ICP within 10-30
min after one oral dose of 1.O-1.27 g/kg glycerol.
This was associated with a rise in serum osmolal-
ity of 19.1 mOsm/L and an average rise in plasma
glycerol concentration of 1.45 mg/ml at 60-90
min. Virno, et aI6O administered 30% glycerol and
20% sodium ascorbate to 16 glaucoma patients
in doses of 0.6 g/kg glycerol and 0.28 g/kg
sodium ascorbate. The maximum effect oc-
curred between 30 and 90 rnin and persisted for
about 6 hr.
Comment
Because of the efficacy of P-blocker topical
eye drops in long term control of glaucoma, glyc-
erol is used primarily for acute control prior to
surgical intervention. It can be administered in
oral doses of 1.O-1.5 g/kg and should be availa-
ble in the ophthalmologist’s It has also
been useful in producing ocular dehydration
prior to cataract surgery.
Hepatic Coma
Prompted by a 31% mortality from cerebral
edema seen in 92 cases of death from fulminant
hepatic failure, Record, et aP9 treated 5 patients
in severe hepatic coma with 50 g of glycerol as a
10% i.v. solution over 24 hr. They found no
improvement in the level of consciousness. In 2
normal subjects given the same dose, plasma
osmolality did not change while increased doses
produced intravascular hemolysis. No conclu-
sions can be drawn from the limited clinical expe-
rience other than to say that glycerol may have
potential use. It should be administered cau-
tiously, because its metabolism may be impaired
by severe liver injury.
Diabetes Mellitus
The metabolic effects of glycerol on diabetic
patients was first explored by Freund.l0He admin-
istered 25-50 g orally 4 times daily in place of
isocaloric amounts of dextrose during partial
insulin withdrawal in 4 ketosis-prone diabetics.
Ketone bodies in blood and alveolar air de-
creased to normal values. He also found an aver-
age of 85 g/day decrease in glycosuria in these
patients and in an additional 3 who had failed to
develop ketosis during partial insulin withdrawal.
This suggested that glycerol is metabolized
through carbohydrate pathways without req u i r-
ing insulin. Glycerol, however, has not gained
157
acceptance as an alternate carbohydrate source
in diabetic diets.
D’Alena, et alz administered 2 g/kg orally to a
diabetic who subsequently developed ketoacido-
sis which resolved within 24 hr after stopping
glycerol and starting insulin. Sears64treated one
patient with diabetes and elevated ICP from
bilateral carotid occlusion. The patient received
50 g orally every 6 hr and developed severe non-
ketotic hyperosmolar hyperglycemia and eventu-
ally died.
Comment
Glycerol is a reduced sugar capable of being
partially metabolized without insulin. However,
as Searse4 points out, “its continuous gluconeo-
genic effect may constitute a sufficient diabeto-
genic stress to exhaust pancreatic beta cell insu-
lin especially in the maturity onset diabetic. In
time, t h e gluconeogenic a n d antiketogenic
effects of glycerol teamed with its moderate
osmodiuretic effect may set the stage for the non-
ketotic hyperosmolar hyperglycemia state in the
maturity onset diabetic.” Substitution of glycerol
in diabetic diets seems impractical, and its use in
diabetics with cerebral edema seems potentially
hazardous.
Preparation
At Columbus Children’s Hospital, i.v. glycerol
is prepared by adding 100 g of glycerol and 45.45
g of anhydrous dextrose to 1 liter of water to
yield a 10% glucerol/5% dextrose solution. Based
on the clinical situation sodium chloride is then
added t o make a final solution of 10% glycerol in
dextrose 5% with sodium chloride 0.45-0.9%.
Oral solutions of 50% glycerol are prepared by
mixing with orange or lemon juice to lessen the
very sweet taste and decrease nausea and
vomiting.
Summary
Glycerol is a potent osmotic dehydrating
agent. It lowers intraocular and intracranial pres-
sure within 10-30 rnin of an oral or intravenous
dose.
Glycerol peak serum concentrations corre-
spond to a simultaneous increase in serum
osmolality. The absolute increase in serum
osmolality required to lower ICP is unclear, as
some of its effect may be via alterations in brain
metabolism and blood flow.
In patients with relatively intact blood brain bar-
riers, a single 1 g/kg dose of glycerol adminis-
tered orally over 20 rnin or i.v. over 30+0 rnin is
generally effective in lowering ICP for 2-4 hr.
ICP declines continuously during a constant
rate i.v. infusion as long as the glycerol concen-
tration in the brain or CSF is not high enough to
158 PHARMACOTHERAPY VOLUME1, NUMBER
equalize or reverse the osmotic gradient. In
patients with intact blood brain barriers, the ini-
tial dehydrating effect may be neutralized after
4 4 hr of a constant rate infusion. In patients with
marked alterations of the blood brain barrier, the
gradient may be reversed by this time.
When small or infrequent doses of glycerol are
used, diuresis is minimal. At large doses, up to
one-half of the administered drug may appear in
the urine, but the diuresis with renal electrolyte
loss is still clinically manageable.
Notable toxicities in man include intravascular
hemolysis, hemoglobinuria, renal damage, hyper-
glycemia, and hyperosmolality. The first three
are not seen with oral use and are greatly mini-
mized when glycerol is given i.v. in dextrose 5%
with sodium chloride 0.45C).9°/~at a rate of 5 6
mg/kg/min. In severe cases of elevated ICP rates
as high as 33 mg/kg/min may be required, but
the therapeutic benefits seem to exceed the risks
of limited hemolysis and reversible renal impair-
ment. Hyperglycemia is generally not a problem,
except in diabetics. Hyperosmolality and re-
bound cerebral overhydration are potential prob-
lems of all osmotic dehydrating agents, which
can be minimized by administering glycerol in as
small amounts and as infrequently as clinically
allowable.
Glycerol has been effective in lowering ICP in
patients with Reye’s syndrome, stroke, encephali-
tis, bacterial aseptic and tuberculous meningitis,
pseudotumor cerebri, CNS tumors, and SOL. It is
also useful in lowering intraocular pressure in
glaucoma and shrinking the brain prior to neuro-
surgical procedures. In addition, glycerol offers
potential advantages over mannitol in many of
these clinical settings. More data are required to
assess its efficacy in brain asphyxia and hepatic
coma. Its use in controlling cerebral edema in
diabetes seems potentially hazardous.
The key to the success of glycerol therapy in
severe cases of elevated ICP is to individualize
the dose in each patient by frequently measuring
serum glycerol concentrations or serum osmolal-
ity and utilizing ICP monitoring.
Acknowledgment
The authors thank Beverly Reshan for her tireless help in
the preparation of this manuscript.
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2, SEPTEMBER/~CTOBER
1981
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160 PHARMACOTHERAPY VOLUME 1, NUMBER
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Case Report
Malignant Liver Tumor
Associated With
Oral Contraceptive Use
Malignant liver tumors in women using oral
contraceptives have been rarely reported.’+ Here
we report an additional case.
A 38-year-old white female was admitted to
hospital at Group Health Cooperative of Puget
Sound with probable superficial thrombophle-
bitis of the lower legs of approximately two
months’ duration and also a firm mass in the epi-
gastrium. In the week prior to admission she had
nightly fever with some sweating and chills.
The patient had used oral contraceptives for
ten years, but had discontinued them approxi-
mately one month prior to admission. Her past
medical history was unremarkable. She was a
nonsmoker and an occasional drinker. There
was no family history of liver disease, cancer, or
other abnormalities.
On admission an ultrasound indicated that the
abdominal mass was solid and an abdominal aor-
togram showed this to be an avascular mass,
most likely in the liver. This was consistent with
an avascular hematoma, but not with a benign
adenoma of the liver. A right venogram showed
venous obstruction at the level of the iliac vein. A
2, S E P T E M B E ~ ~ C T1981
OBER
philus influenza meningitis. Pediatrics. 1977;59:35-9.
83. Mickell JJ. Reye’s syndrome. In: Gellis SS, Kagan BM,
eds. Current pediatric therapy. Philadelphia: W.B.
Saunders; 1980:944.
84. Krupin T. Glaucoma report: Osrnotherapy. Ann Ophthal-
rnol. 1978;10:719.
lung scan showed pulmonary emboli in both
lungs, and anticoagulation was begun.
The day before her death, the patient devel-
oped abdominal pain in the area of the mass.
Anticoagulation was discontinued because of
concern about bleeding into the tumor. The pa-
tient developed a right hemiparesis and had a
definite, continuing decrease in mental status.
Following a left carotid angiogram, the patient
had a cardiac arrest and was unable to be
resuscitated.
Autopsy revealed cholangiocarcinoma of the
liver with intrahepatic metastases and metastases
to peripancreatic lymph nodes.
Jane B. Porter, M.S.
Hershel Jick, M.D.
Boston Collaborative Drug Surveillance Program
Boston University Medical Center
400 Totten Pond Road
Waltham, MA 02154
J. Thomas Ylvisaker, M.D.
Group Health Cooperative of Puget Sound
Seattle, WA 981 12
1. Neuberger J, Portmann B, Nunnerley HB, et al. Oral-con-
traceptive-associated liver turnours: occurrence of rnalig-
nancy and difficulties in diagnosis. Lancet. 1980;1:273+.
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1:1251.
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of oral contraceptives. Gastroenterology. 1977;73:38644.
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dence of carcinoma in a hepatic turnour associated with
oral contraceptives. Br Med J. 1975;4:496-8.