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
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.
Gonadotropin deficiency does not require treatment in the immediate postoperative period.
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
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.
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.
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.