Download Low Specific Gravity Syndrome

Low Specific Gravity Syndrome
H. W. Gillen and C. E. Pippinger
Data strongly suggestthat the longer patients have been treated in New Castle State
Hospital, the higher the probability that they will demonstrate the low specific gravity
syndrome. It is believed that a probably unrecognized alteration in human water
metabolism among institutionalized patients who have chronic, severe epilepsy and
who have been administered anticonvulsant drugs for many years has been documented. The drugs most commonly used within this population are diphenyihydantoin
and phenobarbital. Each compound is reported to affect (albeit oppositely) the release
of ADH, and both affect cellular enzyme systems related to water and/or electrolyte
metabolism.
PATIENTS WITH CHRONIC
NEUROLOGIC
DISEASE
present
an opportunity
for study
of long-range
alterations
in biochemical
and physiologic
phenomena.
If these same patients
have also received
various
pharmacologic agents
for many years,
a second
opportunity
exists
to study
minor toxic effects on human function.
At New Castle State Hospital
(NCSH),
a hospital
for patients
with chronic epilepsy,
both conditions
exist within the patient
population.
For these reasons
tile biochemical
researcim laboratory
of the hospital
began a systematic
screening
program, searching
for biochemical
evidence
of altered
function
that, if
identified,
might
then be correlated
with either
some aspect
of tile
neurologic
disease
or some feature
of time prolonged
adnministration
of
pharmacologic
agents
(mostly
anticonvulsants
and tranquilizers).
Tile first phase of time screening
program
consisted
of examination
of the voided morning
urine specimens
collected
over a 3-month
period
from the entire hospital
population
(N = 793). The screening tests,
performed by classiclaboratory technics,are:
From
the
lad.
46202;
Castle,
md.
Supported
Department
and
the
of
Neurology,
Biochemical
in part
by
U. S. Public
in
at the Symposium
Laboratory,
Oak
Tn(l,amIa University
Laboratory,
Reseai-eh
Health
Service
Grants
School
of
New
Castle
NIl
Medicine,
State
05021-12,
Indianapolis,
Hospital,
New
FR-00057-05,
and
1IE-10401.
Presented
Oak
Ridge
part
National
on
Ridge,
Urinary
Tena.,
403
Constituemits
Nov. 30-Dec.
of Low
1, 1967.
Molecular
Weight,
404
6ILLEN
& PIPPINGER
1)imiitmoplienylhydrazinc
Iiidoxyl
sulfate
I midolic acid spot test
Chemistry
Watson-Schwartz:
chloroform
extinction
Watson.Sehwai-tz
: butanol
extractioti
M eta elmroisma tie sta iii (mmcina my sed iiii it)
Plmenistix
lienesliet’s
Clinitest
Specific
gravity
Omie-diniClmsiollal
chromatography
Pi-ohi
1)11
paper
for
Clinical
amino
ii
test
( ahlomamin )
acids
Initial examination
of time data revealed
a large skew in time distribution of the urine specific gravities
(1)
as seen in Tal)le 1. This was
originally
suspect,
but repeated
tests Oil specimenS
from the same patients at different
meteorologic
seasons,
including
S or more
consecutive
daily collections,confirmed
without
doubt that the observations
were
not spurious.
State hospitals,
regardless
of their purpose,
often have
similarities
not suspected
at first because
of the inadequate
number
of
personnel
available
and fiscal limitations
on diets and drug sources.
Five hospitals
of time State of Indiana
Department
of Mental
Health
cooperated
with mis amid provided,
each data from time routine
morning
urinalysis
from 500 consecutive
patients.
These data failed to (lemonstrate the skew seen originally.
Two community
hospitals
also assisted
us, and analysis
of their data confirmed
our suspicion
that our patient
population
was unique. One of the community
hospitals
was in the immediate
vicinity
and therefore
served as a control for nmeteorologic
and
geographic
features.
NCSH
has its own water
supply
system,
independent
of time local community,
and this feature
of geographic
control
has not yet 1)een studied.
Because
of the possibility
that chronic drug effects produced
the low
urine specific gravities
of our patients,
we searched
for evidence
that
patients
in other state hospitals
on similar
drugs may have similar
changes.
We therefore
obtained
the assistance
of the Director
of Laboratories
at time Craig
Colony
and School,
Sonyea,
N. Y., where
the
patient
population
is almost
identical
(chronic,
severe epilepsy)
and
the drugs used are very similar.
The 500 urinalysis
reports
from Craig
Colony were not different
from normal,
reconfirming
our initial
conTable
Specific
1. SPECIFIC
GRAVITY
DETERMINATIONS
Variation
from
expected
distribution
=
793)
No.
gravity
207*
275*
136
9S
49
24
4
1.000-1.005
L006-1.OlO
1.011-1.015
1.016-1.020
1.021-1.025
1.026-1.030
1.031-1.035
*
(N
by more
than
3 S.D.
Vol. 14, No. 5, 1968
405
LOW SPECIFIC GRAVITY SYNDROME
elusion that the population
of our hospital
appeared
to be unique, for
reasons
unknown
(Table 2).
When
the problem
of low urinary specificgravity is approached
symptomatically,
the differential
diagnosis
lies essentially
between
diabetes
insipidus
due to various
mechanisms
and primary
renal disease. Since niany of time patients
have considerable
brain damage,
it is
also possible
that various
conipulsive
behaviorial
patterns
have developed includimig “psychogenic
diabetes
insipidus.”
However,
time size
of the population
seemed too large, especially
when compared
with other
institutionalized
populations
of brain-damaged
patients
(the mentally
retarded).
Time diversity
of causes
of chronic
epilepsy
requiring
institutionalization
almost preclude
a common
endocrinologic
mechanism
and would negate time probal)illty
of common renal pathologic
processes
accounting
for time low urinary
specific gravity
(or, thin urine).
However, proloimged
administration
of anticoiivulsantdrugs
is associated
with cytologic
changes that might be related
to water amid/or electrolyte
metabolism,
and is associated
w-itim changes
in hepatic
and endocrine
function
(2).
We therefore
began preliniinary
studies of fluid balance to determine
if the patients
had enlarged
or excessive
intakes
related
to their unconcentrated
urine. Once the range of the individual
water balance was
established,
fluid intake
restriction
was imposed
to determine
if the
patients
had the ability to concentrate
their urine. The initial
studies
were uiisatisfactorv
but did indicate
that some patients
could concentrate
tlmeir urine if intake was sufficiently
reduced.
The investigation
was transferred
to time Clinical Research
Center at Indiana
Fniversity
Table
2. MEANS
OF 500 URINESPECIFIC
FROM 9 DIFFERENT
GRAVITY
DETERMINATIONS
HOSPITALS
Nov pilal.’
Name
State hospitals
New Ca.stle State Hospital
Beatty State Hospital
Richmond
State Hospital
Evansville
State Hospital
Fort Wayne
State Hospital
Muscatatuck
State Hospital
Craig Colony
& Sehool (Somlyea,
Special
County
Mean
Epilepsy
NY)
General communils
hospital.sMiami
Valley Hospital
Henry
functiov
retardation
retardation
1 014
1 .015
-
=
is vienifieantl
<.001.
(lifferent
graviiy
1.012*
1 .014
1 .016
1 .015
1 .019
1.020
1 .016
-
Hospital
* New
Castle
State Hospital
mean
lmsespita!s, According
to the (test,
p
Mental
Mental
Epilepsy
opecific
from
means
of each
and
all other
-
4O
GILLEN
Medical Center. Four patients
a preliminary
report
of these
& PIPPINGER
have been
observations.
Clinical
studied
to date.
This
Chemistry
iaier
is
Methods
Patients
were selected
from the NCSH
population
on the basis of
timeir low urinary
specific gravity,
absence of recognized
renal disease,
and freedom
from gross disturbances
of behavior.
The daily fluid intake and output
were measured
during
the entire
hospitalization,
as were the body weight,
urine specific
gravity
and
osmolality,
and usually
the plasma osmolality.
Serum was analyzed
for
sodium, potassium,
chloride,
calcium, phosphorus,
urea, creatinilme,
uric
acid, cholesterol,
protein-bound
iodine,
proteiim electrophoresis,
total
carbon dioxide, protimrombin
time, SGOT, SGPT, alkaline
phospimatase,
and fasting
blood sugar. The 24-hr. urine collections
were analyzed
for
sodium,
potassium,
calcium,
chloride,
phosphorus,
uric acid, urea,
creatinine,
17-hydroxycorticosteroids,
17 ketosteroids,
total amino acids
(ninhydrin),
and by chromatography
for amino acids and mucopolysaccharides.
Multiple
24-hr.
urine
specimens,
with matched
serum
samples,
were serially
studied before and during fluid intake restriction
for sodium,
potassium,
calcium,
chloride,
urea, creatinine,
and phosphorus.
All biochemical
determinations
were made by classic methods.
The following
functional
studies
were done: intravenous
excretory
pyelogram,
T-3 resin
uptake,
urea
clearance,
creatinine
clearance,
electrocardiogram,
and electroencephalogram.
The whole blood volumes
were determined
isotopically.
Classic
hematologic
studies
were made, and time mean corpuscular
volumes
and mean corpuscular
henioglobiii
contents
were calculated.
The total white blood cell count was done and the distribution
of cell
types was counted.
After 3-5 days of observation
without
restriction
of fluid intake,
a
slow, progressive
restriction
was imposed
at 2-day intervals.
ITrine amid
serum analyses
continued
during
this period.
Wimen the patient
could
be maintained
with a fluid output
of less than 2 liters,
time plasma
antidiuretic
hormone
(ADH)
content
was assayed
(3)* At this time
the whole blood volume
was redetermined.
The patient
was then allowed fluid intake and 24-hr. urine specimens
were again collected.
Results
Several
attempts
the control,
without
*Tlmese assays
University
School
were
of
to restrict
restraining
performed
Medicine.
fluid intake
the patient,
by Di-. Ward
W. Moore,
were made at NCSH,
hut
was difficult. On occasion,
T)ep:irtnieiit
of
Physiology,
lioliasia
Vol. 14, No. 5, 1968
LOW SPECIFIC GRAVITY SYNDROME
407
the logistics
of this program
exceeded
the personnel
available.
Changes
in body weight each morning
were used as an index of the efficacy of
fluid restriction,
which, by this criterion,
was unsatisfactory.
The patients, during the periods
of observation,
often excreted
more than the
recorded
intake.
This could be accepted
if one
assumed
the patients
carried an excess water load. The diuresis
would be “proportional”
to
the plasma
osnmolality,
if renal
function
and Al)H
secretion
were
normal.
This appeared
to occur wimen fluid intake control
was “lost.”
Quantitative
fluid and electrolyte
balance
studies
have not yet been
performed.
Four
patients
have
been
studied;
their
abbreviated
clinical
sum-
maries
are in the Appendix.
The first 3 patients
were selected
because
of their persistently
low urine specific gravity.
The fourth
patient
was
selected because it appeared
that after only 2 months of hospitalization
her urine specific gravity
had decreased
from time normal
values originally measured
at the time of her admission
to NCSH. The initial blood
and urine studies
of constituents
that changed
duritmg fluid restriction
are found in Tables 3 amid 4. The serum amid urine biochemical
values
from the first 3 patients
after significant
fluid restriction,
when the
plasma ADH was assayed
are given in Tables 5 and 6.
All patients
had daily, 24-hr. excretions
of sodium, calcium, and
chloride that were low to low-normal,
according
to our laboratory
Table
3. SERUM
Patient
Na
D.W.
D.B.
N.D.
AW.
135
137
140
140
*
CONSTITUENTS
IN PATIENTS
C!
4.1
4.0
43
4.3
Creatininet
102
102
102
103
Fiuw
WITH UNLIMITED
Caiciumt
Ureaf
9.5
9.3
8.9
9.5
7
It)
9
S
0.85
0.81
0.62
060
INTAKE
Ovmolality
(mosm./kg.)
284
291
292
275
Intake
(L.)
6.6
6.9
4.9
3.25
in mEq./L.
tin
mg./l00
Table
ml.
4.
URINE
CONSTITuENTS
IN
PATIENTS
WITH
UNLIMITED
Fi,umn
iNTAKE
Ormol‘ii its’
K
C1
112
82.6
112
1.2
0.3
110
152
130
71.5
62.0
499
110
154
137
1.57
0.96
1.12
0.28
Patient
Na
D.W.
D.B.
N.1).
A.W.
*
In mEq./24
hr.
tin gm./24 hr.
Urine/serum
osmolality.
Creatininef
Csilciumt
-
0.04
Uresmt
-
9.588
8.45
9.05
(moon,./
kg.)
Output
(L.(
Specific
gravity
182
6.7
1.002
180
218
750
7.7
4.6
3.9
1.004
1.003
1.020
i/NI
064
0.62
0.75
2.87
408
GILLEN
Table
5.
SERUM
& PIPPINGER
Clinical
AFTER FLUID
CONCENTRATIONS
Chemistry
RESTRICTION
Damp!ality
(mosm./
CressPatient
Na’
K’
(‘1’
D.W.
D.B.
N.D.
150
139
142
4.7
4.2
4.3
102
102
106
ti,sinet
Cahiumt
0.86
0.58
0.66
11
II
11
-
9.6
5.8
intake
(pu.
kg.)
(L.)
ml.)
257
255
307
2.3
2.6
2.9
2.2
4.3
0.9
Ice,t
In mEqJL.
*
tlmmm
./lOOml
Table
6. URINE
CONCENTRATIONS
AFTER FLUID
RESTRICTION
Oumolality
Patient
.‘sa’
K’
Cl’
Creatini net
1).W.
D.B.
N.1).
184
235
62.8
78
67.2
59.9
198
280
62.4
L66
0.89
1.15
In mEq./24
*
Caiciumt
(movm./
kg.)
Ureat
-
-
0.16
0.02
9.43
4.95
548
352
312
Output
(L.)
Specific
1.7
1.8
7.1
gravity
1
81
1.010
1.005
1.012
L91
1.22
1.02
hr.
tIn mg./24 hr.
osmolality.
Urine/serum
standards.
The urine osniolality
was often low on admission
with unfluid intake. With fluids administered ad lib,the patients
consumed
betweeim 5 and 12 L./day
and excreted
similar
volumes.
The
fourth patient, who appeared to be starting this abnormality, after
continued
observation,
had relatively
normal
rellal
functioim and water
restriction
was miot mitiated
at this time.
restricted
Fluid restriction
was imposed
after time urea and creatrnnie
clearance
studies
were completed
(Table 7) ammdthe initial whole blood volumes
determined.
Although
intake control was attempted
rigorously,
output
measurements
were mucim more likely to be correct
and daily body
weights frequently failed to correlate w-iththe recorded fluidbalance
sheets per 24 -hr. period.
Table
7.
UREA
AND
CREATININE
Jiefore
CI.E.’SRANCES
AND WHOLE
Clessr,s ore
iI’hoic
Whole
Putie,st
(‘
1).W.
D.B.
N.D.
A.W.
*
Urea
normal)
99.9
99.0
112.0
133()
l’mom mmomogram.
BLOOD
(.reats,a,,,e
(ml. mm.)
171.0
89.6
l49.t)
170.0
\OLUMES
revtriction
blood
volume
(‘vi.)
blood coin me (ml.)
after re.vtrjctjon
--
Calculated
5040
4534
4342
4400
Expected’
3700
4231
3348
4205
Calculated
Expected#{176}
4200
3700
4332
4085
3406
3348
No restriction
Vol. 14, No. 5, 1968
409
LOW SPECIFIC GRAVITY SYNDROME
Discussion
In all patients,
the urinary
constituents
per
24 hr. were less thami
expected;
timis was especiallyso for the chloride.
The sodium was almost
always
at the lower end of the expected
rammge. If this constitutes
a
signiflcaimt discrepancy
from time normal
is not yet determined.
Cross
checks were made in two separate
laboratories,
and we therefore
believe
that this population
may represent
several unexpected
problenms, as yet
unsolved.
\Vhen water restriction
imposed,
only 1 of the 3 1)atielltS ever
had an elevated
urine osmolalitv
al)ove 400 mosm./kg.,
or aim increased
urnme specific gravity
above 1.012. Time urine-to-osmolality
ratio failed
to differentiate
ADH-deficiellcv
diabetes
insipidus
after water deprivalion as predicted
by Frasier
et at. (1) Only 1 of time 3 patients
fulfilled
the criteria,
ojyn
that were used to in(licate
a normal
ability
to form
a concentrated
urine. This was iii spite of the normal venous A1)H levels.
Other criteria
of renal function
were all within
normal
limits.
This
.
particular
literature
disorder
of renal fuiictiomm has
to time best of our knowledge.
not
been
described
in the
Time inflimence of time anticollvulsant
drugs on renal function
without
time development
of systemic
lupus erythematosis
syndrome
is poorly
documented.
Lee et at. (:l) reported
that intravenous
dipimenyhimydantoin
HCI, 250 mg., produced
a prompt
increase
in free water
clearance.
Diphenylhydaiitoin
is reported
to inhibit
ADH release
which should
enhance water excretion,
while according
to Kleenman amid Fichman
(6),
phenobarbital
is considered
a potent
stimulus
to AT)H release.
Some of time alterations
iii hepatic
enzymatic
activity
imave l)een recently described
by Zeidenberg
et a!. (7). induction
of increased
activity rates of enzymatic
systems
is now an accepted
concept
and has
occasionally
been demonstrated
using some of the anticonvulsarit
drugs
(8). How this may be related
to our observation
of a large number
of
patients
who do not normally
concentrate
their urine remains
to be
determined.
Appendix
Patient
D.W.
(IUMC
424216) was a 35-year-old
Caucasian
male who had been well
until age 7, at which time generalized seizuresbegan without obvious cause. He has 1
feeble-minded sibling.In retrospectit is now believedthat his growth
and development
may have been retarded before the onset of the epilepsy; he is now moderately
mentally
retarded (IQ estimated at 70). He was admitted
to NCSH
in 1941. He has about 2
seizures (major) a year and takes diphenylhydantoin
(100 mug. h.i.d.),phenoharbital
(100 ng. t.i.d.),
and chlorpromazine hydrochloride (50 mg. q.i.d.).
The general and neurologic examinations were within normal limits.Serology, hemograms, routine urinalysis.
410
GILLEN
& PIPPINGER
Clinical
Chemistry
and X-rays of the chest and skull were all normal except for the low urine
specific
gravity
and an increased MCV (115).
Patient
D.B. (TUMC 424286)
was a 56-year-old
Caucasian
male who had been well
until age 12, at which time generalized
seizures began for no apparent
reason. The family
history
is negative
fornervous
system
disease.
He was adlnitted
to NCSH in 1931 and is
now considered
moderately
retarded
mentally.
For the past 2 years he has had very rare
seizures
while taking
the following
medications:
diphenylhydantoin
(100 mg. t.i.d.),
phenobarbital (100 mg. q.i.d.),
and chlorpromazine
hydrochloride
(50 111g. t.i.d. and
h.s.). He has been on a 1500-cal.,
salt-free
diet for the past 2 years. The general
and
neurologic
examinations
were within
normal
limits
(IQ estimated
at 85). Serology,
heniograms,
X-rays of the chest and skull, and routine urine analysis were normal except
for the low urine specific gravity.
Patient
N.D. (IUMC 426304), a 32-year-old
Caucasian
female, was admitted
to NCSH
in 1944. The falllily
history
was negative
for disorders
of the central
nervous
system.
Her seizures began 5 days following
birth and recurred
for several days. She was then
seizure-free
until age 3 and has had approximately
20 seizures
a year since. The seizures
are focal in type and start with paresthesia
in the right hand, followed by tonic fiexion
of the right hand and arm. A “porencephalic
cyst” was demonstrated
in the left cerebral
centroparietal
lobe by pneumoencephalography.
She is mentally
retarded
(IQ estimated
at 65) and is unable to write or read sentences.
General physical
examination
is within
normal limits. The neurologic
examination
reveals alternating
strabisnlus,
inability
to
optically fix on the midline when the abducting
eye is positioned
laterally,
and hypoactive
reflexes. Her present
medications
are: phenobarbital
(100 mug. h.s.), diphenylhydantoin
(100 mg. t.i.d.), and trifluoperazine
(5 mg. q.i.d.). The serology
and routine
urinalysis
were normal except for the low urine specific gravity.
She has had a mild hypoehrornic,
niicroeytie
anemia for several years, with modest leukopenia.
X-rays
of the chest are
normal.
X-rays
of the skull reveal some probable
inner-table
thinning
over the left
centroparietal
lobe of the cerebrum.
Patient
A.W. (IUMC 428055), a 22-year-old
Caucasian
female, was admitted
to NCSH
in October 1967. She was considered
to have been in normal health until age 13 at which
tilne
3 types of seizures developed.
These did not interfere
with her schooling,
and she
graduated
from high school in 1963 at the age of 18. Since graduation
the seizures
have
progressed
in frequency
and severity, and the patient now shows evidence of deterioration
of mental skills (IQ estimated
at 85). Physical
examination
revealed
an obese female
with normal secondary
sexual characteristics.
Neurologic
exanmination
revealed
moderate
mental retardation,
slurred speech, ataxic and dysmetric
gait and limb movements,
and
moderate
decrease in muscle power in her legs. The muscle stretch reflexes were hypoactive-more
so in the legs. No abnormal
reflexes were present.
Seizure frequency
now
is 10 per month and she takes the following
drugs for seizure control:
methsuximide
(300 ing. t.i.d.), phenobarbital
(200 mg. h.s.), and ethosuximide
(250 mg. t.i.d.). Serology,
hemogram,
and routine urinalysis
were normal except for the low urine specific gravity.
This patient
has specifically
been selected for study because in the 2 months following
admission
(average)
her urine specific gravity decreased
from 1.024 on 3 consecutive
on 5 consecutive
days. X-rays of the chest and skull were within
days to 1.009
normal limits.
References
1. Pippinger,
C. E., Smith, A. M., Morley,
anticonvulsant
drugs:
I. Alteration
Neurology
17, 316 (1967).
G. K., and Gillen,
of urine
specific
H. W., The chronictoxicityof
gravity
ill
epileptic
patients.
Vol. 14, No. 5, 1968
2.
3.
4.
5.
6.
7.
8.
LOW SPECIFIC GRAVITY
411
SYNDROME
Milliehap,
J. G., “Anticonvulsant
Drugs.”
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