Pituitary hormone deficiencies are
of significant concern in the management of patients with pituitary
tumours. Fortunately, many patients undergoing transsphenoidal surgery
have microadenomas and do not have significant pre- or postoperative
endocrine deficiencies. However, patients with larger tumours, and some
of those with hypersecreting states, have abnormalities that need
endocrine attention before surgery, immediately after surgery, and on a
continuing basis. The routine use of corticosteroids and the long plasma
half-life (7 days) of thyroxin mean that the appearance of
adrenocorticotropic hormone (ACTH) and/or thyroid-stimulating hormone
(TSH) deficiency in the immediate postoperative period may be of little
importance, whereas acute deficiency of the posterior pituitary
octapeptide vasopressin may result in a life-threatening disturbance of
water balance. Beyond the immediate postoperative period, the management
of deficiencies of ACTH, TSH, gonadotropin, and growth hormone (GH)
assumes a greater significance in the long-term follow-up of patients.
Preoperative Hormone Therapy
Preoperative assessment includes
attention to specific problems associated with pituitary tumours,
including diabetes mellitus, hypertension, diabetes insipidus (DI),
hypothyroidism (rarely hyperthyroidism), and adrenal insufficiency. Many
tests are available for the evaluation of pituitary function. In the
preoperative period, the most informative studies are those for ACTH
reserve, thyroid function, and electrolyte balance.
Because the surgical procedure may
involve either manipulation or removal of the anterior lobe of the
pituitary gland, all patients, regardless of preoperative
hypothalamic-pituitary-adrenal (HPA) axis testing, receive steroid
replacement to provide adequate glucocorticoid concentrations during the
perioperative period. The benefit of supplementing steroids in patients
with normal preoperative function has not been established, particularly
when high doses are given to patients undergoing adenomectomy. However,
supplemental steroids are routinely administered preoperatively
(dexamethasone 10 mg parenterally or per os the evening before surgery)
to all patients, including those with microadenomas. Although this
approach is probably not necessary in most instances, it provides
steroid coverage for patients who show partial or complete ACTH
deficiency on preoperative testing, as well as for those who become
deficient during surgery.
If diabetes mellitus is present,
appropriate insulin coverage will be necessary. The hypothyroid patient
receives thyroid replacement beginning 4 to 6 weeks before elective
surgery to achieve an euthyroid state. Thyroid replacement is never
given without complete adrenal reserve function testing or replacement,
since thyroid therapy increases the need for adrenal function and may
precipitate an adrenal crisis. Diabetes insipidus can be controlled with
aqueous pitressin or with vasopressin (DDAVP), but is rare in previously
untreated patients with pituitary tumours.
Intraoperative Hormone Therapy
Steroids such as dexamethasone in a dose
of 10 mg are given early in the operative procedure and are repeated in
4 h if the operation lasts that long. Administration of fluids during
transsphenoidal procedures is calculated to include maintenance
requirements and replacement of blood loss and fluid deficit. Some
patients may have taken nothing by mouth for as long as 12 to 15 h
before surgery. It is therefore important that they receive additional
fluid during the induction of anaesthesia to replace the deficit and in
anticipation of blood loss. Although operative blood loss is usually 50
to 100 ml, it can be extensive and acute, so blood should be available.
If diabetes insipidus is present, the urinary losses must be replaced as
well.
Diabetes insipidus is not an uncommon
sequela of transsphenoidal procedures, particularly hypophysectomy.
Although its onset is usually on the first or second postoperative day,
occasionally occurs during anaesthesia or in the recovery room.
Measurement of urine output is important, but insertion of a urinary
catheter is usually unnecessary.
Immediate Postoperative Replacement Therapy
Pituitary-Adrenal Dysfunction
Glucocorticoids are routinely
administered to all patients following surgery for a pituitary tumour,
regardless of preoperative HPA axis testing.
If the pituitary-adrenal function is
normal prior to microadenoma surgery (e.g., for treatment of a
prolactinoma or acromegaly), it is normal afterward in most cases.
Moderate-dose dexamethasone (4 to 8 mg per day) is commonly used in
these patients during and immediately after surgery. The dosage is
rapidly tapered to maintenance levels (0.75 mg) by the third and fourth
postoperative days. This rapid tapering usually averts adrenal
suppression and decreases the incidence of glucose intolerance.
Following microadenoma surgery in which the normal gland was well seen
and not overly manipulated, the patient is discharged without
replacement medication. The possible need for steroids and the symptoms
of insufficiency are discussed with the patient and family upon
discharge; the patient is given dexamethasone tablets.
Patients with an ACTH-secreting
microadenoma (Cushing's disease) are not totally withdrawn from
steroids. Rather, if a total adenomectomy has been achieved, normal or
slightly greater than normal replacement therapy is required for 3 to 6
months. If the patient is not temporarily hypocortisolemic
postoperatively, it is unlikely that a cure has been achieved. The
hypocortisolemia usually lasts 3 to 6 months.
Patients with preoperative
pituitary-adrenal insufficiency usually require replacement steroids
following surgery. In these patients and in those subjected to total
hypophysectomy, the high dose steroids (dexamethasone 4 to 8 mg per day)
are tapered to replacement levels, which are adjusted before discharge.
Patients receiving adrenal replacement are always informed of the
probable need for additional hormones in times of stress. In patients
with significant suprasellar tumour extension, the dosage is tapered
more slowly, since high-dose steroids may offer the additional benefit
of reducing local brain swelling caused by the tumour and the
manipulation of surgery.
Pituitary- Thyroid Dysfunction
Following surgery for a pituitary tumour,
the patient who is preoperatively euthyroid may become deficient in
thyroid-stimulating hormone; this is not important in the immediate
postoperative period, however, because thyroxin has a plasma half-life
of 7 days. In contrast, a patient whose chronic preoperative secondary
hypothyroidism has been untreated or treated inadequately with
replacement thyroid medication may develop complications in the
immediate postoperative period due to or aggravated by thyroid
deficiency.
The hypothyroid patient may exhibit
impaired consciousness postoperatively, ranging from mild lethargy to
coma, because of the various effects of thyroid deficiency on drug
metabolism, respiratory function, fluid and electrolyte balance, and
cardiac out-put. Hypothyroidism may reduce drug metabolism, potentiating
the effects of sedative, analgesic, and anaesthetic medications; it may
reduce the ventilatory drive to a hypoxic and, in the severely
hypothyroid state, a hypercapneic stimulus; and it may impair urinary
dilution and sodium excretion, an effect that may produce hyponatremia
and cause reduced myocardial contractility, which decreases cardiac
output and cerebral perfusion. It is preferable to treat hypothyroid
patients for a minimum of 4 to 6 weeks preoperatively with sodium
L-thyroxin to avoid postoperative complications associated with
hypothyroidism. When this is not possible, a daily dose of thyroxin
(0.025 to 0.1 mg per os) is started in the immediate postoperative
period. The age of the patient, duration of hypothyroidism, and evidence
of coexisting coronary artery disease determine the precise initial
dosage. Sodium L-thyroxin may be administered intravenously when the
patient is unable to take medication orally. This dose is one-half to
three-fourths the oral dose, since only 60 to 80 percent of the oral
sodium L-thyroxin is absorbed from the gastrointestinal tract. The
management of myxedema coma has been most successful when up to 0.5 mg
of intravenous sodium L-thyroxin is given first to replenish the total
body thyroxin pool.
Patients requiring preoperative thyroid
medication or those who have had a total hypophysectomy are usually
started on replacement thyroid treatment as soon as they can take oral
medications. Thyroid hormone therapy is rarely needed after microadenoma
surgery. A slight fall of T3 and T4 values can be seen 1 week after
operation, probably owing to a transient disturbance in pituitary TSH
function. A falsely low T4 can also be due to phenytoin administration.
Adrenal reserve function should always be tested before initiating
thyroid replacement, because the latter increases the need for adrenal
hormone and may precipitate an adrenal crisis. When thyroid replacement
is needed, adrenal replacement is usually required as well.
Hypogonadism
Gonadotropin deficiency does not require
treatment in the immediate postoperative period.
Diabetes Insipidus
The incidence of DI in the immediate
postoperative period varies with the nature of the procedure. In total
hypophysectomy patients, it may be as high as 37 percent. In 250
microsurgical procedures for adenoma, the incidence of DI reported by
Wilson and Dempsey was 9.2 percent; of these, 3.6 percent had partial
and 2.0 percent had total persistent DI. After most transsphenoidal
procedures, DI is self-limited and resolves within a week to 10 days.
This may simply reflect the extreme sensitivity of the
hypothalamic-neurohypophyseal unit to local alterations in blood flow.
oedema, and traction on the pituitary stalk. Permanent disturbance of
antidiuretic hormone (ADH) secretion is due to direct damage to the
neurohypophyseal unit and depends much more on the original size and
location of the tumour and the extent of surgical resection. High-dose
glucocorticoids and phenytoin may interfere with the secretion of
vasopressin as well.
Prompt, accurate diagnosis and aggressive
treatment are essential to prevent the extreme alterations in
electrolyte and water balance that may accompany these syndromes.
Usually DI is easily recognized by the polyuria in the early
postoperative period. It commonly occurs 12 to 24 h after pituitary
surgery. Urine volume is frequently more than 150 ml/h. with an
abnormally high serum osmolality (>295 mosmol/kg). an elevated serum
sodium level (> 148 meq/litre). and an inappropriately dilute urine <300
mosmol/litre).
In a patient undergoing water diuresis
due to overhydration during surgery and the early postoperative period,
an erroneous diagnosis of DI is avoided by allowing the diuresis to
continue until a state of mild serum hyperosmolality is achieved. A
normal or high serum osmolality and high urine osmolality suggest an
osmotic diuresis, most often due to osmotic agents such as mannitol or
to glucosuria in a diabetic patient. Basic requirement of successful
management include meticulous intake and output records, once- or
twice-daily measurements of weight and of serum electrolytes and serum
and urine osmolalities, and replacement of fluid loss as free water (5%
dextrose in water if given intravenously). Patients who are not very
sick and who can take oral fluids should be allowed to regulate their
own intake and water balance. As soon as possible, their intravenous
fluids should be removed and their glucocorticoid dosages tapered. By
the second or third postoperative day, the polyuria and polydipsia have
usually attenuated to several litres a day and do not require treatment.
If the patient can self-regulate fluid intake, it is best not to overuse
vasopressin; in this situation the diabetes insipidus is more of an
annoyance. Only when adequate fluid intake cannot be maintained because
of lethargy or an impaired thirst mechanism is specific drug therapy
instituted in the early postoperative period. The rationale for this
approach is that DI may be transient or may progress rapidly to the
interphase of endogenous ADH secretion. However, since the consumption
of large quantities of fluid may be poorly tolerated and may interfere
significantly with sleep, hormonal substitution therapy may be
indicated, regardless of the urinary volume.
The preferred agent for treating acute
postoperative DI in the patient who has had a transsphenoidal procedure
is DDAVP (desmopressin). DDAVP has replaced aqueous vasopressin as the
preferred agent for treating both acute and chronic postoperative DI.
The usual dose is 2 to 4 µg (0.5 to
1 ml) intravenously or 20 to 40 µg
(0.2 to 0.4 ml) intranasally in divided doses b.i.d.
In cases of severe water loss and
hypernatremia, the deficit in total body water must be corrected by
giving intravenous fluids in addition to DDAVP. Generally, the deficit
in total body water is calculated, and one-half of the fluid deficit is
corrected over the first 24 h.
Also used to treat DI is aqueous
vasopressin (20 U/ml), because its action is of brief duration. The
usual dose is 0.1 to 0.3 ml every 4 to 6 h. The lower dose may produce a
more diluted urine, and its effect dissipates more rapidly, minimizing
the potentially dangerous complication of water intoxication and the
less dangerous, albeit disturbing, problem of rapid shifts in serum
sodium concentration. As the effect wears off, water diuresis is allowed
to persist for up to several hours in anticipation of a return of
endogenous ADH secretion.
Triphasic DI is unusual with
microadenoma surgery but may occur with larger tumours. After several
days, DI may disappear and be followed by the syndrome of inappropriate
secretion of ADH (SIADH). If this possibility is not anticipated, the
patient may rapidly become water-intoxicated and severely hyponatremic
on parenteral fluids. Several days of inappropriate vasopressin
secretion are usually followed by reappearance of transient or permanent
diabetes insipidus.
Syndrome of Inappropriate ADH
Secretion (SIADH)
Preoperative medications (narcotics and
barbiturates), anaesthetic agents, and surgical stress stimulate ADH
secretion and may cause hyponatremia and a low urinary volume in the
early postoperative period. SIADH resulting from surgical irritation of
the hypothalamic neurohypophyseal unit must be considered in the absence
of an identifiable explanation for hyponatremia. The diagnosis is
supported by the demonstration of low serum osmolality, inappropriate
high urine osmolality, and a urinary sodium concentration above 20
meq/litre.
SIADH is usually transient, occurring
independent of or during the interphase of DI, but it may persist for
months or years following surgery. Appropriate management, like that for
DI, requires frequent measurements of body weight, urine and serum
osmolality, and serum sodium concentration and accurate intake and
output records. The severity of clinical symptoms depends on the degree
and the duration of the hyponatremia. Severe, acute hyponatremia with
serum sodium concentrations of < 120 mmol/litre is characterized by
somnolence, seizures, and coma, and by mortality rates as high as 50
percent in some studies. For this reason, severe, acute hyponatremia
with central nervous system manifestations requires immediate treatment.
Fluid intake should be restricted to
maintain serum sodium in the normal range (usually 0.5 to 1.5 litres per
day). Fluid restriction alone is inadequate therapy if severe water
intoxication occurs with severe hyponatremia (115 to 120 meq/litre or
less) and mental changes or seizures; furosemide diuresis with
electrolyte replacement (3% NaCl) should be instituted. The concurrent
use of hypertonic saline (three times normal) and furosemide has been
proposed as a way to raise serum osmolality without the risk of a large
fluid accumulation. Because furosemide acts by blocking active sodium
transport in the ascending limb of Henle's loop (concentrating segment)
and early distal tubule (diluting segment), it results in a large volume
of a urine that has an osmolality approximately that of plasma. The
combined effect of a hypertonic solute load and high-volume isosthenuric
urine leads to a rapid rise in serum osmolality.
However, care must be taken to avoid
correcting serum sodium concentrations too rapidly to levels above 125
mmol/litre. In dilutional states, brain cell volume is preserved by the
loss of brain solutes. A sodium level of 140 mmol/litre is relatively
hypertonic to brain cells that have become partially depleted of solutes
as a result of hyponatremia. Rapid restoration of serum Na+ levels to >
120 to 125 mmol/litre can thus result in CNS damage such as central
pontine myelinolysis. Although the exact mechanism by which rapid
correction of hyponatremia causes central pontine myelinolysis remains
unclear, the extent and rate of correction of serum Na + is important in
the development of neurological complications. A conservative
therapeutic regimen would be a serum Na+ correction rate of 0.5
mmol/litre until the serum sodium concentration reaches 120 to 125
mmol/litre.
Chronic Pituitary Hormone Therapy
Pituitary-Adrenal Dysfunction
Patients are usually retested for HPA
function 4 to 6 weeks after surgery. Significant drug-related HPA axis
suppression usually rarely occur in patients receiving low-dose
corticosteroids for this period of time. If replacement steroids were
used, they are discontinued 48 h prior to testing.
If adrenal gland unresponsiveness is
suspected. the serum cortisol response to ACTH (Cortrosyn) should
first be assessed. Patients who respond poorly to Cortrosyn are excluded
from further testing of the HPA axis and are maintained on replacement
steroids. A normal or impaired cortisol response to insulin or
metyrapone may be exhibited by patients not tested with Cortrosyn or by
those who show a normal cortisol response to Cortrosyn. Under stress,
patients with an impaired response but normal basal cortisol levels are
at risk of developing acute ACTH deficiency. They are instructed in the
use of supplemental steroids and are routinely retested at 12- to
24month intervals. Patients with low basal levels and impaired HPA
responsiveness are placed on daily physiologic steroid replacement.
Exceptions to this plan of steroid
management and postoperative testing include patients severely deficient
in HPA function preoperatively and those who have had such extensive
tumour resection that the probability of permanent hypopituitarism is
high. These patients are maintained on replacement steroids for life.
Patients undergoing radiotherapy after
incomplete removal of a large pituitary adenoma are maintained on twice
the usual physiologic replacement dose of corticosteroid (e.g.,
dexamethasone 1.5 to 2 mg daily in divided doses) throughout the course
and for 1 week after completion of radiotherapy. The stress of
radiotherapy justifies the use of supplemental steroids in patients who
may have underlying ACTH deficiency. Dosage is then tapered to
physiologic levels over 1 to 2 weeks. Although minor physical changes
resulting from glucocorticoid excess may occur during the period of
radiotherapy, the transient side effects of steroid excess appear to be
outweighed by the improved energy level and sense of wellbeing seen
with this regimen. The prolonged use of supraphysiologic doses of
dexamethasone increases the likelihood of drug induced HPA axis
suppression. Therefore, postoperative HPA axis testing is delayed for 6
months or more in this group of patients.
Patients with secondary adrenocortical
insufficiency may be maintained on steroid replacement therapy using one
of the following regimens: (1) hydrocortisone, 20 mg per os (PO) each
morning and 10 mg PO each afternoon; (2) cortisone acetate, 25 mg PO
each morning and 12.5 mg PO each afternoon; (3) prednisone, 5 mg PO each
morning; or (4) dexamethasone 0.5 mg PO daily at bed time. The most
physiologic form of replacement therapy is with hydrocortisone or
cortisone acetate; the disadvantage of these agents is that they must be
taken twice daily.
An increase in steroid dosage under
stress is required by all ACTH-deficient patients, including those who
have normal basal cortisol levels but an impaired ACTH reserve (and who
are not receiving daily replacement steroids). Patients are advised to
double their steroid dose daily for minor stress (e.g., an upper
respiratory infection) and to triple their dose daily for intermediate
stress (e.g., an infectious illness with fever or a dental or minor
surgical procedure). Major stress (e.g., major trauma or surgery)
usually requires parenteral steroids: 100 mg hydrocortisone three or
four times daily or its intravenous equivalent. All patients should be
provided with Medicalert identification (necklace or bracelet)
indicating deficiency in adrenocortical function, and they should be
instructed in the use of an injectable corticosteroid (e.g.. 4 mg
dexamethasone phosphate) in the event that vomiting precludes ingestion
of an oral preparation. If the patient is unconscious, a relative or
friend may administer the intramuscular dose of dexamethasone prior to
seeking medical care. Patients are also advised not to travel great
distances from convenient access to health care facilities unless
accompanied by someone knowledgeable in the parenteral administration of
glucocorticoids. Mineralocorticoid replacement is not needed in
pituitary ACTH deficiency.
Pituitary- Thyroid Dysfunction
The optimum replacement dose of sodium
L-thyroxin for management of chronic central hypothyroidism is 0.1 to
0.2 mg daily, the variability being due partly to the dependence of dose
on body size. The use of a synthetic thyroxin (T4) preparation is
preferred, because thyroxin administered once daily results in constant
levels ofT4 and T3 in blood. Serum levels of T4 and T3 obtained with
thyroxin can be used to adequately assess thyroid hormone dosage, but
those obtained with preparations containing triiodothyronine cannot be
so used because of the shorter (24-h) half-life of T3. Because pituitary
disease causes TSH deficiency, TSH levels are not helpful in monitoring
thyroxin therapy.
Hypogonadism
Gonadotropin assay, prolactin level, and
testosterone assay in males are useful guides to treatment. The most
sensitive tests of fertility are the sperm count in the male and
menstrual cycles with evidence of ovulation (temperature rise at
midcycle or progesterone elevation at late cycle) in the female. The
concentrations of gonadotropin (luteinizing hormone,
follicle-stimulating hormone) are frequently in the normal range in
pituitary hypogonadism. Androgen concentration partly determines libido
in both sexes. Women with pituitary insufficiency usually do not achieve
normal libido after estrogen replacement alone, because ACTH deficiency
results in a loss of adrenal androgens; approximately one-fourth (or
less) of the testosterone dose given to men is usually required to
compensate for this loss. It may be necessary to inquire specifically
about sex drive, because many patients hesitate to complain about
decreased libido, believing that this is an effect of their illness for
which there is no treatment. Elevated serum prolactin levels also result
in decreased libido. In males who have low testosterone and elevated
prolactin levels, testosterone replacement alone will not restore normal
libido; it is also necessary to lower the serum prolactin level, for
example by using a dopamine agonist.
Chronic replacement therapy consists of
200 to 300 mg testosterone propionate intramuscularly every 2 to 4 weeks
in men and of ethinyl estradiol 20 to 50 µg
or conjugated estrogens (Premarin) 0.625 to 2.5 mg daily in women.
Estrogen treatment is administered to women for 25 days each month, with
oral medroxyprogesterone, 5 to 10 mg daily, added for the last 5 days.
This induces menstrual flow and reverses the endometrial hyperplasia
which may occur when estrogens are administered alone. Alternative
treatments in women are the transdermal estrogen patch (0.05 to 0.1 mg
applied to the skin twice weekly) or one of the combination oral
contraceptives. Oral medroxyprogesterone, 5 to 10 mg daily, should be
given for 5 to 10 days monthly with the estrogen patch to prevent
endometrial hyperplasia.
Oral testosterone is not an effective
therapy for male hypogonadism. Transdermal testosterone skin patches are
in use.
Successful treatment of infertility using sequential
combinations of human menopausal gonadotropin (hMG) and human chorionic
gonadotropin (hCG) in patients who have undergone hypophysectomy is now
well established, so that hypophyseal deficiency need not preclude the
possibility of parenthood. Because of its great expense and the
occurrence, in some women, of ovarian hyperstimulation, this form of
therapy should be administered only by physicians who are familiar with
its application. After treatment, men may successfully impregnate their
partners even when sperm concentration does not exceed 10 x 106
ml. Although clomiphene citrate enhances gonadotropin secretion by
blocking estrogen receptors and therefore the negative feedback of
estrogen, it is of no value in many patients who are infertile after
hypophysectomy, since gonadotropin reserve is often reduced or absent.
Growth Hormone Deficiency
In children with postoperative
hypopituitarism, the focus of treatment is to promote a normal growth
rate by the administration of growth hormone. Recombinant DNA-derived
growth hormone has supplanted pituitary-derived growth hormone as the
agent of choice. Response rates are generally better in younger, more
obese, and more severely deficient children. The recombinant growth
hormone is generally given subcutaneously in doses of 0.3 mg/kg per
week, either daily or tri-weekly. Long-term treatment has been reported
to be free of serious side effects. One report from Japan indicated that
growth-hormone-treated patients had an excess incidence of leukaemia,
but worldwide experience has failed to confirm this association.
In most protocols, therapy is continued
until full growth potential has been realized (closure of epiphyseal
plates on radiologic exam). The maximal effect reported with growth
hormone therapy occurs in the first 3 months, the so-called catch-up
growth period. After the first and each subsequent year of treatment,
growth velocity usually decreases. The use of growth hormone therapy in
adults is controversial and not generally recommended at this time.
Chronic Diabetes Insipidus
Persistence of DI beyond the immediate
postoperative period presages a poor long-term outlook for recovery,
particularly after transfrontal surgery. It is unusual to see permanent
DI in a patient following transsphenoidal pituitary surgery. Several
cases of partial ADH reserve deficiency were seen, which may become more
symptomatic during alcohol ingestion or after an increase in
corticosteroid dosage. Both alcohol and corticosteroids cause a central
inhibition of ADH release.
If a postoperative patient complains of
mild polyuria and polydipsia and if there is a possibility of partial
or, a modified dehydration test is performed. All fluids are withheld
until the specific gravity of three consecutive hourly urine collections
remains constant, usually 6 to 15 h after the start of the test in
patients with partial DI. (In more severe DI, this end point may be
attained very quickly; it is important to monitor body weight before and
during the test, and dehydration should be terminated when 3 to 5
percent of body weight has been lost). Serum and urine osmolality are
measured simultaneously, and DDAVP, 10 µg
intranasally, is given. Serum and urine osmolality are then measured for
an additional 2 to 4 h. Prior to DDAVP administration, patients with
central or nephrogenic DI show an abnormally high serum osmolality (>295
mosmol/kg) and inappropriately low urine osmolality <600 mosmol/kg and
often much lower). Following DDAVP, there is a 10 percent or greater
increment in urine osmolality in patients with central, but not with
nephrogenic DI. The treatment of choice for chronic DI is DDAVP, which
is virtually free of side effects except for the headache that may occur
in some patients. Moreover, in the doses usually prescribed, DDAVP does
not raise blood pressure and pulse rate or cause abdominal pain. Good
control is usually achieved with 20 to 40 µg
given intranasally in divided doses twice a day, although once daily
dosing may suffice, and occasionally three doses per day may be needed.
Therapy is best initiated at night. When an evening dose that controls
nocturia has been established, a second daily dose is added, usually in
the morning.
Chlorpropamide (an oral sulfonylurea used
to treat diabetes mellitus), clofibrate (an agent used to treat
hyperlipidemia), and carbamazepine (an anticonvulsant drug useful in the
management of tic douloureux), have demonstrated an antidiuretic effect
that is useful in the treatment of patients with mild chronic DI. In
addition, thiazide diuretics at low doses (e.g., hydrochlorothiazide 25
mg PO daily) can be effective in reducing the symptoms of mild, partial
ADH deficiency. Chlorpropamide alone (50 to 500 mg daily) is effective
in mild degrees of DI. but its use has been limited by life-threatening
hypoglycemic reactions, particularly in patients with
panhypopituitarism, and by overhydration resulting in symptomatic
hyponatremia. The usual dose of clofibrate is 500 mg 2 to 4 times daily
and, of carbamazepine, 400 to 600 mg daily.
Chronic SIADH
Fluid restriction is an effective
means of maintaining serum sodium levels in the normal range. Lithium
carbonate and demeclocyline have also been used in SIADH because of
their action on the renal tubule leading to nephrogenic DI. The
therapeutic dose for demeclocyline is 600 to 1200 mg daily (in divided
doses) and, for lithium carbonate, 600 to 900 mg per day. Patients
receiving lithium should have frequent determinations of serum levels,
and the dose should be adjusted to maintain a therapeutic range.
