Vol. 72 • No. 4
CASE REPORTS
been taking a hormone for six years, although it is
uncertain whether the lipid-rich cells reached the
proportion of foam cells. Dallenbach found that the
"entire stroma had undergone change into foam cells"
in a woman with endometrial adenocarcinoma who had
taken diethylstilbestrol for 20 years. 8 Harris found
foam cells in the stroma of cervical polyps from women
taking estrogens, but gives no further clinical details. 9
If the lipid accumulation is related to exogenous
estrogen administration, the same questions regarding
the pathogenesis of the lipid accumulation still exist.
Whatever the mechanism for lipid formation, we conclude that the morphologic features indicated that the
vast majority of foam cells are of endometrial stromal
origin. The qualitative identity of the cytoplasmic
characteristics of the normal-sized stromal cells with
the large polyhedral foam cells forms the basis for this
interpretation. The cells with sizes and shapes intermediate between these two extremes further support
this conclusion.
References
1. Atkinson WB: The histochemistry of normal and abnormal
growth in human endometrium. Texas Rep Biol Med
13:603-610, 1955
2. Baron DA, Esterly JR: Histochemical demonstration of lysosomal hydrolase activity in endometrial mononuclear cells.
11. Abnormal endometrium. Am J Obstet Gynecol 123:797803, 1975
3. Black J, Heyns OS, Gillman J: The value of basal fat in the
human uterus as an indicator of optimum progesterone
activity. J Clin Endocrinol 1:547-555, 1941
633
4. Budny NN: Pyometra with massive foam cell reaction: A case
report. Am J Obstet Gynecol 112:126-129, 1972
5. Craig JM, Danzinger S: Histological distribution and nature of
stainable lipids of the human endometrium. Am J Obstet
Gynecol 93:1018-1023, 1965
6. Dallenbach-Hellweg G: Uber die Schaumzellen im stroma des
endometriums: Vorkommen und Histochemische Befunde.
Virchows Arch Pathol Anat 338:51-63, 1964
7. Dallenbach FD, Rudolph HG: Foam cells and estrogen activity
of the human endometrium. Arch Gynaekol 217:335-347,
1974
8. Dallenbach-Hellweg G: Histopathology of the Endometrium.
Second edition. New York, Springer-Verlag, 1975, p 176
9. Harris HR: Foam cells in the stroma of carcinoma of the body
of the uterus and uterine cervical polypi. J Clin Pathol
11:19-22, 1958
10. Isaacson PG, Pilot JR, Gooselaw JG: Foam cells in the stroma
in carcinoma of the endometrium. Obstet Gynecol 23:9-11,
1964
11. Moyer DL, Mishell DR Jr: Reactions of human endometrium
to the intrauterine foreign body. II. Long-term effects on the
endometrial histology and cytology. Am J Obstet Gynecol
111:66-80, 1971
12. Papanicolaou GN: Observations on the origin and specific
function of the histiocytes in the female genital tract.
Fertil Steril 4:472-478, 1953
13. Salm R: Macrophages in endometrial lesions. J Pathol Bacteriol
83:405-409, 1962
14. Schiller WL: Uber Xanthomzellen im uterus. Archiv Gynaekol
130:346-375, 1927
15. Sweat ML, Young RB: Low magnitude transformation of
estradiol to estrone in human endometrium. Biochem Biophys
Acta 296:189-195. 1973
16. Thrasher TV, Richart RM: An ultrastructural comparison of
endometrial adenocarcinoma and normal endometrium. Cancer 29:1713-1723. 1972
17. Tseng L. Gurpide E: Estradiol and 20 a-dihydroprogesterone
dehydrogenase activities in human endometrium during the
menstrual cycle. Endocrinology 94:419-423. 1974
Propylene Glycol as a Cause of an
Elevated Serum Osmolality
LEONAS BEKERIS, M.D. CATHERINE BAKER, PH.D., JOHN FENTON, PH.D., DOUGLAS KIMBALL, PH.D., AND
EDWARD BERMES, PH.D.
Bekeris, Leonas, Baker, Catherine, Fenton, John, Kimball,
Douglas, and Bermes, Edward: Propylene glycol as a cause of
an elevated serum osmolality. Am J Clin Pathol 72: 633-636,
1979. Two severely burned patients experienced the onset of
marked hyperosmolality during topical treatment with a cream
containing silver sulfadiazine as an antimicrobial agent. Serum
Received September 18, 1978; accepted for publication December
7. 1978.
Supported in part by NIH Research Training Grant in Clinical
Chemistry 5 TOI GM02112-05.
Address reprint requests to Dr. Bermes: Departments of Pathology
and Biochemistry, Loyola University of Chicago, 2160 South First
Avenue. Maywood, Illinois 60153.
Departments of Pathology and Biochemistry,
Loyola University Medical Center,
Maywood, Illinois
samples from both patients were studied for the presence of
substances absorbed from the vehicle of the cream. Propylene
glycol, in concentrations which were high enough to account for
the difference between calculated and measured osmolality,
was demonstrated in the sera of these patients by gas chromatography. (Key words: Propylene glycol; Osmolality; Osmolar
discriminate.)
0002-9173/79/1000/0633 $00.70 © American Society of Clinical Pathologists
634
BEKERIS£7"/tL.
350 :
2
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400:
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A.J.C.P. • October 1979
MEASURED
300250
CALCULATED
FIG. 1. Osmolality values for thefirstpatient
as measured by freezing-point depression. Calculated osmolalities have been obtained using
the formula in the text.
200;
150-
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100
50
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DELTA OSMO.
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I 2 3 4 5 6 7 8 9 O II 12 13 14 15 16 17 18 19 2021222324
Days of Hospitalization
OSMOLALITY, which measures the number of particles in solution, is an important tool in the management of trauma and surgical patients, especially the
burn patient. It is usually measured in terms of freezing-point depression, since this colligative property is
most easily measured and does reflect true osmolality.818
Since serum osmolality is a measure of the number of
particles in solution, it may be approximated using
several formulas that involve the concentration of certain constituents that are routinely determined. 17 A
commonly used and reasonably accurate formula5 is:
Osmolality = 1.86 Na + (Glu/18) + (BUN/2.8) + 9
However, the calculated osmolality does not take
into account unknown solutes present under abnormal
conditions, and is usually slightly lower than the measured osmolality."' 17 For many years, it was thought that
a marked difference between measured and calculated
osmolalities ("delta osmolality" or "osmolar discriminate") had an ominous prognostic significance/ 11418
Dorwart and Chalmers 5 stated that it is rare for patients who are not in shock to have measured osmolalities that differ by more than 15 mosm/kg from
calculated osmolalities unless they suffer from ethanol
intoxication. They, as well as Boyd and co-workers, :i
felt that the predictive value of the osmolar discriminate, if any, is restricted to patients in shock.
This report presents biochemical findings in two
cases of patients with extensive burns in whom striking
elevations of serum osmolality developed while they
were receiving topical treatment with a silver sulfadiazine cream.
Report of Two Cases
Case 1. A 39-year-old Caucasian man, who had been in good
health previously, received multiple burns when his bed caught fire
while he was smoking. On admission to the burn unit at Loyola
University Medical Center, the patient was conscious, dehydrated,
and had second- and third-degree burns covering 80% of his body
surface. Flexible bronchoscopy revealed extensive injury to the
tracheobronchial tree. Immediate therapeutic measures were instituted for compensation of the dehydration and prevention of infection. The therapeutic program included massive topical administration (to as much as 25 pounds per day) of sulfadiazine silver
cream on the burned areas. After four days of hospitalization, measured serum osmolality was noticed to be climbing, and it continued to increase, reaching a peak of 420 mosm/kg by the twelfth
day. During all this time, the patient remained conscious and was
able to sit by himself. Serum ultrafiltration with fluid replacement
was performed, but no noticeable change in osmolality was observed.
Terminally, the patient had sepsis, disseminated intravascular
coagulation, renal failure, and a pulmonary embolism. He died 21
days after admission to the unit. Autopsyfindings,in addition to the
burns, included a pulmonary embolism with pulmonary infarction,
an organizing renal infarct, and gram-negative septicemia.
Case 2. A 14-year-old Caucasian boy, previously in good health,
was admitted to the Loyola University Medical Center burn unit
after suffering burns in a gasoline fire. Upon admission, the patient
was alert, responsive, and able to move all extremities. The blood
pressure was 90/60 mm Hg, pulse 130/min, temperature 37.9 C,
respiratory rate 26/min. Second- and third-degree burns covered
approximately 90% of the total body surface, sparing the feet,
posterior scalp, and waistband. Therapy, which in this case also included large amounts of sulfadiazine cream, was started immediately.
By the fifth day of hospitalization, osmolality had increased to
395 mosm/kg, and it continued to climb until it reached a peak of
463 mosm/kg on the fourteenth day of hospitalization. Despite intensive therapeutic efforts, the patient's condition continued to deteriorate, and he died 19 days after admission. Autopsy revealed
gram-negative septicemia and bronchopneumonia.
CASE REPORTS
Vol. 72 • No. 4
635
500-
5
FIG. 2. Effect of the addition of propylene glycol to serum on osmolality as
measured by freezing-point depression
(- • -) and by vapor pressure (- O -).
i
o
o
£
400
300-
O
200
50
100
Propylene Glycol Concentration ( m m o l / l )
Methods
Osmolalities were routinely determined by the freezing-point depression method on an Osmette A (Precision Systems, Inc.) standardized with solutions
containing 500 and 100 mosm/kg. Vapor pressure osmolalities were determined on a Wescor 5100 standardized according to manufacturer's instructions.
Gas-liquid chromatography was performed on a
Hewlett Packard 5830A chromatograph equipped with
a flame ionization detector. The column was packed
with Chromosorb 102® and was 1.8 m long with a 4-mm
inner diameter. The propylene glycol standard was
made from reagent-grade propylene glycol (Harleco) at
a concentration of 0.5 ml/1 (7.0 x 10 -3 mmol/l). The
standards and sera were injected directly onto the
column.
The retention time of the propylene glycol was 4.6
min under the following conditions:
Injector temperature:
Carrier gas:
Flow rate:
Oven temperature:
Flame ionization
detector temperature:
250 C
nitrogen
45 ml/min
215 C
250 C
Discussion
Figure 1 summarizes the values of serum osmolality
measured by freezing-point depression throughout the
hospital stay of the first patient. The calculated value
for osmolality was obtained by use of the formula given
above. Within a week after the trauma, "delta osmolality" had increased to a value of about 100 mosm.
In an attempt to explain the rather large "delta osmolality" value, the contribution of medications to the
osmolar discriminate was considered. The massive
topical administration of the sulfadiazine silver cream
was noted. Previous investigators had concluded that
significant amounts of silver11 or sulfadiazine" could be
absorbed by the patient through the burned areas. Although the concentration of silver in the serum was
found to be 7.4 x 10~:! mmol/l, and sulfadiazine levels
on the order of 0.3 mmol/l were found, these would
account for an increase in osmolality of less than 1
mosm. A major constituent of the cream's vehicle is
propylene glycol, a polyol which is miscible with water
and could therefore be readily absorbed by the tissues
in areas where skin had been burned away. In view of
the well-known phenomenon of increases in serum osmolalilty by ethanol and other volatile substances, 24r '7.i2.i3.i5,i6 propylene glycol was considered a possible
source for the elevated osmolality.
It is known that volatile substances are measured as
solute in freezing-point osmometry and, therefore, any
such volatile substance will make a contribution to
osmolality measured by this technic. On the other
hand, when vapor-pressure osmometry is used to measure the osmolality of a solution containing volatile
substances, these substances exert a vapor pressure of
their own and are therefore a part of the solvent. In
these instances, volatile substances contribute less to
the measured osmolality. 1 - 61317 There has been some
636
BEKERIS£7-/ti,.
controversy concerning the relative merits of the two
types of osmometry in cases where volatile substances
are present in serum. 1 ' 6 1 3 1 7 It would seem necessary
merely to be aware of the limitations of each method in
these cases.
In order to determine whether propylene glycol (or
some other volatile substance) might be contributing to
measured osmolality, sera from both patients were
analyzed by both freezing-point and vapor-pressure
osmometry. 1 In Case 1, the vapor-pressure value was
20 mosm/kg lower, and in Case 2, it was 35 mosm/kg
lower, than the value obtained cryoscopically. It was
therefore concluded that the sera of both patients contained a volatile substance, probably propylene glycol.
At this point, a more definitive method for confirming the presence of propylene glycol in serum was
deemed necessary. To this end, the gas chromatographic system described earlier was utilized. When
patient serum was injected directly on the column, a
peak was obtained which had the same retention time
as that of a propylene glycol standard. Quantitation
with an external standard yielded values of 0.1 mol/1
and 0.04 mol/1 propylene glycol for the sera of the first
and second patients, respectively.
As a further verification, propylene glycol was added
to a serum pool and osmolality was determined by both
methods. Figure 2 summarizes the data from this experiment. As can be seen from this figure, the Wescor
Vapor pressure osmometer read consistently lower
than the freezing-point depression instrument. Thus,
propylene glycol could account for the discrepancy between results obtained by use of the two methods of
measuring osmolalities. For one particular sample obtained from the first patient, serum osmolality was 381
mosm/kg by the freezing point depression method and
358 mosm/kg by the vapor-pressure method. From figure
2, it can be seen that a difference of 23 mosm/kg by these
two methods would correspond to a propylene glycol
concentration of about 0.1 mol/1. Propylene glycol was
also demonstrated in the urine and in the ultrafiltrate
from the first patient.
In view of the presence of silver, sulfa, and propylene
glycol, special care was used in both cases in the study
of the tissue sections obtained at autopsy. By light
microscopy, no specific evidence of renal damage attributable to sulfadiazine or propylene glycol9-10,15 was
observed. Al.l changes could be explained on the basis
of autolysis, shock or infarction. Silver deposition was
not observed in any tissue.
Electron microscopic studies were also performed
on the kidneys. Unstained ultrathin sections were examined in an attempt to see electron-dense deposits
indicating silver deposition in the kidneys. These sections, as well as sections stained with uranyl acetate
A.J.C.P. • October 1979
and lead citrate, failed to show metallic deposits or any
other specific change.
Ethanol has been regarded as the most common
cause of an elevated "delta osmolality" or "osmolar
discriminate" in the patient who is not in shock, and
has been the substance most commonly observed where
osmolalities measured by use of different colligative
properties of serum have differed. We have presented
two cases where propylene glycol, absorbed through
the skin, caused hyperosmolahty. This polyol was
demonstrated in the sera of the patients in concentrations high enough to explain the differences in osmolalities obtained using a vapor-pressure instrument
and an instrument that measures freezing-point depression, and to explain the large "delta osmolality" or
"osmolar discriminate."
References
1. Barlow EK: Volatiles and osmometry (cont.) (letter to the editor)
Clin Chem 22:1230-1231, 1976
2. Beard JD, Knott DH, Fink RD: The use of plasma and urine osmolality in evaluating the acute phase of alcohol abuse. South
Med J 67:271-273, 1974
3. Boyd DR. Folk FA, Condon RE, et al: Predictive value of
serum osmolality in shock following trauma. Surg Forum
21:32-33, 1970
4. Champion HR, Caplan YH, Baker SP, et al: Alcohol intoxication and serum osmolality. Lancet 1:1402-1409, June 28,
1975
5. Dorwart WV, Chalmers L: Comparison of methods for calculating serum osmolality from chemical concentrations,
and the prognostic value of such calculations. Clin Chem
21:190-194, 1975
6. Dorwart WV, Chalmers L: Response to Weisberg.17 Clin Chem
21:1185, 1975
7. Glasser L, Sternglanz PD, Combie J, et al: Serum osmolality
and its applicability to drug overdose, Am J Clin Pathol 60:
695-699, 1974
8. Loeb JN: the hyperosmolar state. N Engl J Med 290:1184-1187,
1974
9. Marshall JP, Schneider RP: Systemic argyria secondary to
topical silver nitate. Arch Dermatol 113:1077-1079, 1977
10. Muehrcke RC, Volini RI, Morris AM et al: Acute toxic nephropathies: Clinical pathologic correlations. Ann Clin Lab Sci
6:477-513, 1976
11. Owens CJ, Yarborough DR, Brackett NC: Nephrotic syndrome
following topically applied sulfadiazine silver therapy. Arch
Intern Med 134:332-335, 1974
12. Redetzki HM. Koerner TA, Hughes JR, et al: Osmometry in the
evaluation of alcohol intoxication. Clin Toxicol 5:343-363,
1972
13. Rocco RM: Volatiles and osmometry (letter to the editor).
Clin Chem. 22:399, 1976
14. Rubin AL, Braveman WS, Dexter RL, et al: The relationship
between plasma osmolality and concentration in disease
states. Clin Res Proc 4:129, 1956
15. Ruddick JA: Toxicology, metabolism, and biochemistry of 1,2propanediol. Toxicol Appl Pharmacol 21:102-111, 1972
16. Stern EL: Serum osmolality in cases of poisoning (letter to the
editor) N Engl J Med 290:1026, 1974
17. Weisberg HF: Osmolality—calculated, "delta", and more
formulas (letter to the editor). Clin Chem 21:1182-1185. 1975
18. Weisberg HF: Water, electrolytes, acid-base and oxygen.
Todd Stanford Clinical Diagnosis by Laboratory Methods.
Fifteenth edition. Edited by Davidsohn, Henry. Philadelphia,
W. B. Saunders pp 782-783