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Antidiuretic hormone levels in stroke patients.

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BRIEF COMMUNICATIONS AND CASE REPORTS
Antidiuretic Hormone
Levels in Stroke Patients
Robert J. Joynt, MD, PhD,"t John H. Feibel, MD,"
and Celia M. Sladek, PhD*t
Serum osmolality and antidiuretic hormone (ADH)
levels were determined for 17 patients with cerebral
infarction, 4 with subarachnoid hemorrhage, and 12
controls. The ADH levels were elevated significantly
in the stroke patients. Hyponatremia was not observed.
Stroke patients are at risk for developing electrolyte
disturbances; thus, fluid intake and electrolyte levels
should be closely observed.
Joynt RJ, Feibel JH, Sladek CM: Antidiuretic
hormone levels in stroke patients.
Ann Neurol 9:182-184, 1981
Fluid and electrolyte disturbances, especially hyponatremia, occasionally follow upon either occlusive
or hemorrhagic stroke [ l o , 12, 131. Potentially,
the complication can lead to decreased responsivity,
seizures, or even death [l], with the change in the
patient's clinical state erroneously attributed to the
cerebrovascular disease [ 131.
Poststroke hyponatremia is likely due to the syndrome of inappropriate secretion of antidiuretic
hormone (SIADH). The features of this syndrome
are hyponatremia and serum hypoosmolality with
continued renal excretion of sodium, a urine concentration less than maximally dilute, no clinical evidence of fluid volume depletion, and normal renal
and thyroid function [3,91. T h e exact mechanism responsible for the hyponatremia has not as yet been
determined. The popular theory is that the inability
to excrete water reflects an excess of antidiuretic
hormone (ADH). A defect of intracellular solute
regulation has also been suggested [6].
Many studies o n the occurrence of SIADH have
not measured the A D H level. When A D H has been
measured, it has been found to be elevated 15, 14,
221, or at least high for the corresponding serum osmolality [4, 151. In some patients with high ADH
levels, the hormone may be ectopically produced by
a tumor [17] and the inappropriate secretion may
occur even though the serum sodium level is within
normal limits. Thus, hyponatremia may not be pres-
From the Departments of *Neurology and tAnatomy, University
of Rochester Medical Center, Rochester, NY 14642.
Received July 1, 1980, and in revised form Aug 4. Accepted for
pubiicarion Aug 4 , 1980.
Address reprint requests to Dr Joynt.
182
ent and the usual clinical laboratory determinations
may not be helpful. Because of this possibility, ADH
and serum osmolality levels were determined in a
series of patients with cerebrovascular disease.
Methods
The patients, all adults, were admitted to the Stroke Acute
Care Research Unit of Strong Memorial Hospital. The
control patient population was cared for o n the adult neurology service. The patients were usually admitted within
twelve hours of the onset of their cerebrovascular episode.
I n a few instances, determinations were made after a
further stroke had occurred in the hospital. Control patients had no evidence of either vascular or progressive
central nervous system disorders. Simultaneous samples
were taken for ADH, serum osmolality, and electrolyte
determinations. These were obtained for both patient and
control populations in the morning while the patients were
still recumbent, before any food intake or smoking; both
upright position and smoking will elevate ADH levels. I n
almost all instances, fluid intake was oral and on an ad
libitum basis. No hypertonic soiutions were used in patients requiring intravenous fluids.
ADH determinations o n serum were done by a
modification of the method of Skowsky et a1 122, 231. The
antiserum was made available through the generosity of
T. B. van Wimersa and David de Weid of the University of
Utrecht. The assay has a minimum sensitivity of 2 pgiml
and permits measurement of serum arginine vasopressin
concentrations as low as 1.5 pdml following extraction of 2
ml of serum. In earlier testing of 11 healthy adults o n free
fluid intake, this method gave a mean value of 2.5 pglmi,
which is in close agreement with the normal value obtained
by others L17, 181. Serum osmolality values were determined by the freezing-point method.
Results
Simultaneous ADH and serum osmolality values
were obtained in 17 patients with thrombotic infarction (2 in the brainstem), 4 patients with subarachnoid hemorrhage, and 12 control patients. T h e
values are given in the Figure.
The mean values and standard deviations of A D H
for the three groups of patients were: control, 2.23 2
0.60 pglml; infarction, 4.20 2 2.05 pglml; and subarachnoid hemorrhage, 3.70
0.82 pglml. T h e
probability of the individual stroke groups being of
the same population as the control group is less than
0.005 using Student's t test. There is n o statistically
significant difference between the two stroke groups.
No control patient had an A D H level over 3.2 p d m l ,
while 3 of the 4 patients with subarachnoid hemorrhage and 11 of the 1 7 with infarction did. The 2
patients with brainstem infarcts had levels of 2.7 and
1.8 pdrnl, within the normal range.
Serial observations in 18 patients showed A D H
levels to be highest immediately after the stroke or,
in some instances, after extension of the infarct o r
0364-5 134/81/020182-04$01.25 @ 1980 by the American Neurological Association
*
9
8
0
7
6
0
5
4
A
0
A
3
A
0
0
2
0.8
0
1
230
240
250
260
210
280
290
300
310
320
mOsm/L
Osmolality iniOmlL) and A D H h e l s (pglrnl! in stroke Patients and controls. (Triangles = subaruihnnid hemorrhage;
closed circles = infarction: open circles = controlpatients.l
rebleeding. The levels often remained elevated for
four or five days. O n e patient had an A D H level of
4.4 pglml, which increased to 8.5 pglml immediately
after occlusion of one carotid artery.
Osmolality values for the three groups were: control, 282.7 ? 10.9 mOsm/L; infarction, 277.8 :t 20.1
mOsm/L; and subarachnoid hemorrhage, 278.5 f 35
mOsmlL. There were no significant statistical differences between any two groups. Mean values for
serum sodium levels were: control, 136 mEq/L; infarction, 136 mEq/L; and subarachnoid hemorrhage,
138 mEq/L. There were no serum sodium levels
below 134 mEq/L in the patients with stroke.
Discussion
Although the patients with stroke had higher levels
of A D H , hyponatremia was not encountered. The
serum osmolality did not differ between stroke patients and controls, although 10 of the 2 1 stroke patients had levels below 280 mOsm/L compared with
4 of the 12 controls. It is iikely that hyponatremia
was not encountered because of the common practice
of restricting fluids in these patients and closely
monitoring their electrolyte status. Since the A D H
levels were high in the stroke group in relation to
their coexisting serum osmolality levels, their secretion of A D H was inappropriate. This was noted particularly in those with osmolality levels below 280
mOsm/L. Robertson et a1 [ 181 have established near
280 mOsm/L as the osmotic threshold for suppressing A D H secretion. They also found that A D H
ranged from 0.5 to 5.0 pglml in normal subjects with
a maximally dilute to a maximally concentrated urine.
The normal A D H level with ad libitum fluid intake is
near the middle of that range [ 181. This value agrees
with our determination of 2.5 pg/ml for normal volunteers and 2.23 pglml for our patient control population. Therefore, the concept of SIADH must be revised to include instances in which A D H is high for
the concomitant serum osmolality values [ 151. These
patients are unable to suppress A D H release properly and to excrete a water load normally. Stroke patients are thus susceptible to electrolyte abnormalities in spite of a usually normal laboratory value
of serum sodium.
The mechanism for the inappropriate release of
A D H has not been clarified. Joynt et a1 [13] and later
Imbeau and Rock [12] suggested that it might be secondary to damage to the anterior hypothalamus. This
was postulated for those cases of subarachnoid
bleeding secondary to aneurysm rupture, particularly
with anterior communicating artery aneurysms.
Crompton 171 pointed out the high incidence of damage in the area of the hypothalamus: 61% overall in
his series, with 22 ruptures among 32 anterior communicating artery aneurysms. Such damage would directly involve the magnocellular nuclei (supraoptic
and paraventricular) where A D H is produced. Damage that causes isolation of this area could result in
denervation hypersensitivity of the neuronal elements with subsequent increased activity.
Brief Communication: Joynt et al: ADH Levels in Stroke
183
This theory of direct damage would not explain the
release of A D H in most cerebral infarctions. Segar
and Moore 12 1Jand Auger et a1 121 suggested that the
inappropriate A D H release may be due to positional
factors. They demonstrated that prolonged recumbency may lead to rionfilling of the capacitance vessels of the thorax. Since the volume receptors are
important in regulating A D H release, their lack of
stimulation results in release of the hormone. They
showed that this excess release of A D H stopped if
the patient's head was lowered and the capacitance
vessels were filled.
Other mechanisms are also possible. Brain injury, including stroke, causes release of catecholamines [8], cortisol [8], and cyclic nucleotides [20],
all of which may enhance the release of A D H . Experimentally, carotid occlusion releases A D H [16].
Recently, Weindl et a1 [24]found a more ubiquitous
distribution of vasopressin ( A D H ) neurons in the
brain. Damage to areas other than the hypothalamus
could result in nonspecific release of A D H . Such a
response would be analogous to the release of tissue
enzymes observed after muscle, heart, and liver damage. There are many inputs to the magnocellular nuclear areas from various parts of the brain [ 111. Damage to inhibitory areas could lead to disinhibition,
with release of inappropriate amounts of A D H .
Which of these factors, if any, leads to SIADH in
stroke patients is open to speculation. In many instances, SIADH does not result from untrammeled
release of A D H , but is due to resetting of the osmoreceptor 1191. This would cause A D H to be released at a lower level of osmolality and might account for the higher A D H values, in the normal
range of serum osmolality levels, seen in the patients
reported here. Robertson et a1 1191 suggested that
the threshold could be altered by a lesion affecting
the volume regulatory pathways that interact with the
osmoreceptors to effect release of A D H . 'They
further suggested that the loss of osmotically active
substances from the osmosensitive cells would reduce the level of extracellular tonicity that activates
the osmoreceptor.
Supported by Grants 5 P I ~ N S - I I 1 1 0and AM-I9761 from the
National Institutes of Health and the Waasdorp Center for Stroke
Research. Dr Sladek is the recipient of an N I H Research Career
Development Award. Dr Joynt is A Senior International Fogarty
Scholar.
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References
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Vol 9
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k e b r u d r y 1981
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