Neurohypohpysis

The hypothalamus forms the inferior and lateral walls of the third ventricle, extending from the optic chiasm to the caudal border of the mamillary bodies (a distance of about 10 mm in the adult), and is divided into three regions: (1) the supraoptic area dorsal to the optic chiasm, (2) the central tuberal region, and (3) the caudal mamillary region. The neurohypophysis consists of a portion of the base of the hypothalamus, the neural stalk, and the neural (posterior) lobe of the pituitary gland. The median eminence of the tuber cinereum, while anatomically part of the neurohypophyseal portion of the hypothalamus, is involved primarily in the regulation of anterior pituitary function.

The hypothalamus contains small nerve cells with no distinguishing features, called parvicellular neurons, scattered throughout its substance; it also contains large neurons, called magnocellular, which are clustered together to form prominent nuclei. These magnocellular neurons are located in the paired supraoptic nuclei (SON) situated above the optic tract and in the paraventricular nuclei (PVN) immediately beneath the ependyma of the third ventricle. The unmyelinated nerve fibers from these large cells descend through the infundibulum and neural stalk to end in the neural lobe of the pituitary gland, forming the supraopticohypophyseal and paraventriculohypophyseal tracts. The vasopressinergic and oxytocinergic fibers in the external lamina of the median eminence appear to arise primarily from the medial parvicellular group in the PVN. This neuronal system is the probable source of the vasopressin transported in the portal vessel circulation to the anterior pituitary. Magnocellular neuronal perikarya that stain for vasopressin predominate in both the SON and the PVN. However, only scanty oxytocinergic cell bodies are found in the SON, most being located in the PVN.

In 1982, vasopressin and the opioid peptide dynorphin were localized to the same magnocellular neurons by immunohistochemical techniques. Glucagon, cholecystokinin, and angiotensin II-like immunoreactivities have also been identified in magnocellular neurosecretory systems, but the functional significance of this coexistence has not yet been established. The neurohypophyseal hormones are synthesized as part of a large precursor glycopeptide (propressophysin and pro-oxyphysin), which also contains carrier proteins (nicotine-sensitive neurophysin for vasopressin and estrogen-sensitive neurophysin for oxytocin). These are then transported in secretory vesicles (packets of hormone and carrier protein) down the axons for storage in the posterior pituitary gland.

Experimental sectioning of the hypophyseal stalk results in the accumulation of colloid substance granules varying from 500 to 2000 nm in diameter above the transection, and their disappearance below it. The stored vesicles in the nerve endings are situated on delicate membranes that are separated from the basement membranes of adjacent capillaries by a narrow perivascular space. This anatomic juxtaposition allows the posterior lobe neurons to act as endocrine organs-that is, they become cells of the type referred to as neuroendocrine transducers. which convert neural information to hormonal information. Indeed, the impetus for release of these stored posterior lobe hormones is an action potential originating in the neuronal cell body.

The neurons of the neurohypophysis are primarily regulated by β-adrenergic (inhibitory) and cholinergic (stimulatory) neurotransmitters. α-Adrenergic agonists and prostaglandins of the E group also release ADH. However, magnocellular neurons are also stimulated by neuropeptides, particularly angiotensin II and endogenous opioid peptides (endorphins), which may function as physiologic modulators of posterior pituitary hormone secretion.

Although it is now clear that vasopressin has a wide distribution in the central nervous system, where it may act as a neurotransmitter or neuromodulator in a way quite unrelated to its posterior pituitary function, its most established function is its role as antidiuretic hormone (ADH). Following its release from the posterior pituitary, ADH is transported in the systemic circulation to the distal renal tubules and collecting ducts, where, after binding to specific receptors of the V2 type on the cell membrane, it activates adenylcyclase; this leads to the generation of cyclic adenosine monophosphate (cAMP), which operates as an intracellular second messenger. The hormonal activity causes a change in the configuration of the luminal membrane of the cells of the distal renal tubules and collecting ducts, altering their permeability to water, urea, and possibly sodium. The net effect of this chain of events is increased reabsorption of water from the nephron back into the circulation.' Other vasopressin receptors of the V1 (pressor) type are located on vascular smooth muscle and induce vasoconstriction by enhancing phosphatidylinositol turnover and increasing the concentration of free cytosolic calcium.

When plasma vasopressin levels are under 1 pg/ml, there is maximal free water excretion, with the urine volume theoretically capable of reaching 20 litres per day, although in reality a volume in excess of 8 litres per day is rare even in the absence of detectable circulating vasopressin. When the vasopressin level is between 1 and 2 pg/ml, its relationship with urine volume is inverse and exponential, with slight elevations in plasma vasopressin causing dramatic reductions in urine volume. A plasma vasopressin level of 5 pg/ml or greater results in maximum urine concentration, which can be 1000 mosmol/kg H2O if renal function is normal.

Endogenous prostaglandins (mainly E2) seem to antagonize the effect of vasopressin-activated cAMP, whereas inhibitors of prostaglandin synthesis such as indomethacin enhance the effect of vasopressin. Other substances or conditions that impair the generation or action of vasopressin include hypercalcemia, hypokalemia, and the administration of lithium or the antibiotic demeclocycline.

This effect of lithium and demeclocycline accounts for their therapeutic effect in clinical states of vasopressin "excess," as in the syndrome of inappropriate ADH secretion (SIADH).

The interplay between thirst and antidiuretic hormone-the two most important factors in maintaining fluid balance-is controlled by information received from both osmoreceptors and volume receptors. The osmoreceptors are situated in the anterior hypothalamus but appear to be outside the blood-brain barrier. When the plasma osmolality increases by as little as 1 to 2 percent, the osmoreceptor cells shrink, leading to synthesis of vasopressin and its release into the systemic circulation. A decrease in osmolality has the opposite effect. The prime factor regulating ADH secretion is plasma osmolality. In the event of severe hypovolemia (a loss of more than 10 to 15 percent of blood volume), the maintenance of volume takes priority over the maintenance of osmotic balance. There is some evidence that volume receptors may themselves have a regulatory effect on osmoreceptor function.

The volume receptors affecting ADH secretion are located peripherally: in the left atrium, in the pulmonary veins, and, as stretch receptors, in the arterial circulation. These receptors respond to changes in volume and arterial pressure and, through neuronal pathways, lead to an increase or decrease in ADH secretion to maintain normal volume. There is also a temperature-dependent oropharyngeal reflex involved in the suppression of vasopressin. Ingestion of cold water leads to a prompt suppression of plasma vasopressin even before the water is absorbed from the stomach.

The renin-angiotensin system is also concerned with the preservation of volume. If renal perfusion is decreased (e.g., as a result of decreased blood volume), more of the enzyme renin is released. Renin activates the conversion of angiotensinogen to angiotensin I (a decapeptide), which in turn is converted to angiotensin II (an octapeptide). Angiotensin II acts on the hypothalamus not only to promote ADH secretion but also to increase thirst, both effects designed to restore volume.

It should be noted that the hypothalamus contains an independent neuronal renin-angiotensin system, all the components of which arise in situ. It appears likely that both central and peripheral angiotensin II regulate thirst and vasopressin secretion, but the relative physiologic importance of each system has not been established.

A wide variety of pharmacologic agents affect the release or action of ADH. Thyroid hormone and cortisol seem to modulate the osmotic set-point for the release of ADH. Thus, hypothyroidism and hypoadrenocorticism enhance ADH release, which contributes to the hyponatremia seen in these disorders. Glucocorticoid excess raises the osmotic threshold for ADH release and can exacerbate a borderline diabetes insipidus. Drugs that enhance ADH release include nicotine, chlorpropamide, cholinergic agents, clofibrate, barbiturates, morphine, anesthetic agents, and carbamazepine. Agents that decrease the release of ADH include water, ethanol, phenytoin, and anticholinergic agents.

"Higher" neural centers have an effect on ADH secretion, as evidenced by the increased ADH release seen in response to pain, nausea, and stress (both emotional and physical) and the ability to bring about either diuresis or antidiuresis experimentally by hypnotic suggestion or psychological conditioning.

It is of interest, and perhaps of some clinical importance, that when the neurohypophyseal system is isolated from the neural input of other parts of the brain, the system is more active electrically, and ADH secretion is increased. This hyperfunction of the neurohypophyseal system caused by isolation or "denervation" may explain in part some of the abnormalities of ADH secretion seen in some patients with brain injuries.

There is now much evidence in experimental animals that vasopressin plays an important role in regulating adrenocorticotropic hormone (ACTH) secretion, acting directly through V3 receptors on the corticotropes. Vasopressin colocalizes with corticotropin releasing hormone (CRH), the 41-aminoacid peptide in the parvicellular neurons of the PVN. Vasopressin potentiates ACTH release induced by CRH, especially in response to insulin-induced hypoglycemia.

Oxytocin, like vasopressin, is a member of the large family of neuropeptides that are distributed throughout the central nervous system. In extrapituitary locations, oxytocin probably functions as a neurotransmitter or neuromodulator; this role is quite separate from its established physiologic role related to reproduction. The hormone has a selective effect on the smooth muscle of the uterus and plays a major role in the expulsion of the fetus and placenta. Labor can begin in a patient with deficient posterior pituitary function but may be prolonged. It is possible that other hormonally induced changes in the uterus make it sensitive to normal concentrations of oxytocin, and that uterine contraction becomes enhanced only when the proper hormonal priming has taken place.

Oxytocin also causes contraction of the myoepithelial cells of the breast. These cells cause the glands to express their contents into ducts so that the milk will accumulate in the nipples. Once nursing has started, the release of oxytocin seems to be stimulated via a neural reflex arc that is activated by sensory nerve endings in the nipple.

Vasopressin and oxytocin are secreted independent of each other. This fact is demonstrated in lactating women by two circumstances: (1) The normal sucking stimulus induces milk letdown without accompanying antidiuresis; and (2) intravenous hypertonic saline infusion increases ADH production without producing milk letdown.

The requirements for normal water balance include adequate ADH production, normal osmoreceptors in the hypothalamus, normally functioning nephrons, a relatively normal renal medulla such that the osmolar gradient necessary for water reabsorption can be maintained, a normal thirst center, and the ability to respond to thirst in an appropriate way. It is clear that the clinical picture of diabetes insipidus (DI)-polyuria secondary to water diuresis and polydipsia-may result from dysfunction in any of these areas.

Central (neurogenic) DI is caused by an insufficient production of ADH in the hypothalamus. Inability to secrete ADH results in excretion of a dilute urine. Failure to counter this fluid loss results in dehydration, hemoconcentration, and hypovolemia. Destruction of the hypothalamic centers or division of the supraoptic tract above the median eminence causes permanent DI. Transection below the median eminence, including removal of the posterior pituitary lobe, causes only a transient polyuria, apparently because enough ADH can be released from fibers at the level of the median eminence. Nephrogenic DI (caused by impaired activity of vasopressin at the level of the kidney) may be the expression of a congenital abnormality or may result from an acquired disorder (e.g., chronic renal disease, electrolyte disorders, administration of certain drugs).

DI usually becomes clinically apparent because of polyuria. The differential diagnosis of polyuria includes diabetes mellitus, hypercalcuria, psychogenic polydipsia, chronic renal failure, and the various forms of DI. Abnormalities of glucose metabolism, electrolyte balance, and renal function can usually be ruled out with routine laboratory studies. The next step is to determine whether solute or water excretion is causing the diuresis.

When solute excretion is responsible for the diuresis, the urinary specific gravity is usually between 1.010 and 1.035; urine osmolality is usually greater than 300 mosm/kg; and the serum sodium level is variable-for example, it may be low in hyperglycemia with glucose diuresis or high in subjects dehydrated by high-protein tube feedings. In mild solute diuresis the urine osmolality may be high, for example, 800 mosmol/litre; as the rate of solute excretion increases, however, an increasing amount of water will escape reabsorption in the proximal tubule and the urine will approach isotonicity. In the neurosurgical patient population, the major causes of solute diuresis are osmotic diuretics, hyperglycemia, and corticosteroid deficiency leading to an inability to retain sodium.

If polyuria is secondary to water diuresis, as in DI, the urinary specific gravity is usually between 1.001 and 1.005; urine osmolality is usually between 50 and 150 mosmol/kg; the serum sodium value is generally increased; and thirst is usually a prominent clinical feature. The common causes of water diuresis in the neurosurgical patient include (1) DI (Table-1); (2) chronic renal insufficiency - in which case the patient is usually azotemic with abnormal renal function studies; (3) nephropathy secondary to multiple myeloma, amyloidosis, sickle cell disease, radiation nephritis, or systemic lupus erythematosus or following the relief of obstructive uropathy; (4) the recovery phase of acute tubular necrosis (perhaps secondary to ischemic or toxic injury); and (5) fluid overload- a particularly important consideration in the perioperative period, when the patient's fluid intake is parenterally administered and not regulated by the thirst mechanism.

Simultaneous measurement of urine and serum osmolality can provide valuable information. In all instances of water diuresis the urine is hypoosmolar, but the serum osmolality is normal or increased in DI and is usually reduced in compulsive water drinking (Table-2). When the serum is hyperosmolar, the administration of ADH will differentiate between central DI (there will be a response of water conservation) and nephrogenic DI (no response to ADH). Patients with psychogenic polydipsia may be resistant to exogenous vasopressin because of diminished renal medullary tonicity from chronic water intake. Compulsive polydipsia is most often secondary to a behavioural disorder, but the possibility of habitual water drinking secondary to an organic abnormality of the thirst center should also be considered.

It should be kept in mind that hyperosmolality of the serum seen in association with hyperosmolality of the urine is caused by lack of water intake and not DI. This situation can be seen in patients with a defective thirst mechanism, essential hypernatremia, or an impaired level of consciousness such that they do not recognize their thirst and in those who either have no access to water or are unable to drink it.

Essential hypernatremia is a disorder that occurs in the elderly and can be confused with DI. Despite the elevation of the serum sodium level, there is euvolemia, normal renal function, and hypodipsia, and the urine is less concentrated than would be expected from the serum sodium value. There is reduced vasopressin release in response to the serum osmolality. This condition occurs in a wide variety of systemic illnesses, but is especially apt to occur following head trauma and surgery in the hypothalamic area.

In the immediate postoperative period, a brisk diuresis may occur as a result of overhydration with isotonic fluids given during surgery. This diuresis can generally be distinguished from DI by measuring the serum sodium level. which is usually under 140 meq/litter. However, the diagnosis of mild or compensated DI can be difficult because the serum osmolality may be relatively normal despite hypo-osmolar urine. It is in these less obvious cases that provocative testing is required; a modified dehydration test is usually adequate. For this test, the patient is deprived of all fluids until three consecutive hourly urine specimens have the same specific gravity, usually at 6 to 12 h from the start of testing in patients with partial DI; sooner in patients with severe DI. The body weight is measured before the test and hourly during it, and no more than a 3 to 4 percent loss of body weight is allowed. When the test is terminated, the serum and urine osmolality are measured simultaneously, 1-deamino-8-D-arginine vasopressin (desmopressin, DDAVP) is given (1to 2 µg by subcutaneous or intravenous injection or 10 µg by intranasal spray), and the serum and urine osmolality are then measured hourly for an additional 2 to 4 h. Patients with DI from any cause generally have an elevated serum osmolality (more than 295 mosmol/kg, and often much higher) prior to DDAVP administration. In central DI, an increase in the urine osmolality by at least 50 percent, to reach a level of 600 to 800 mosmol/kg, will occur, whereas in nephrogenic DI, the DDAVP will increase the urine osmolality by less than 10 percent. In some cases, measurement of the endogenous plasma vasopressin level and its responsiveness to dehydration can help to distinguish cases of compulsive water drinking or nephrogenic DI from central DI.

The clinical expression of DI in postoperative and post-traumatic situations can be variable, and the permanence of the DI cannot always be predicted in the early stages. It is well documented that an occasional patient may require months or even years to regain an adequate level of ADH function. It should also be kept in mind that patients who do not have clinically obvious problems may have a transient episode of DI in response to appropriate stimuli. Such stimuli may include increased ethanol intake or a significant increase in corticosteroid dosage.

The clinical course of DI after head injury or surgery affecting the hypothalamic area usually follows one of four major patterns:

1. The most common situation is transient polyuria starting 1 to 3 days after surgery and lasting 1 to 7 days. This may follow traction on the pituitary stalk, as may occur during transsphenoidal surgery for a pituitary tumor, and seems to be an expression of hypothalamic rather than pituitary dysfunction. The onset and duration of this syndrome are compatible with the onset and dissolution of local edema.

2. A triphasic pattern has been described both in humans and in experimental animals. Polyuria beginning 1 to 2 days after surgery lasts 1 to 7 days and is followed by a period of normal urinary output lasting up to several days; abnormally large urinary output then resumes and persists. This triphasic response was produced in experimental animals by transection of the pituitary stalk and destruction of the hypothalamic median eminence if the posterior lobe of the pituitary gland was left in place; if the posterior lobe was removed, there was an immediate and permanent polyuria. The intermediate phase (also called the interphase) of normal urinary output seems to be secondary to the release of ADH that was stored in the posterior pituitary gland; when this ADH has been used up, permanent DI ensues.

3. Polyuria may begin within the first 2 to 3 postoperative days and be followed by a small decrease in total urinary volume over the next several days. This is seen in patients with a partial ADH deficiency that is magnified in the initial stages because of superimposed local edema.

4. Permanent polyuria develops within the first 2 to 3 postoperative days and continues thereafter with no intermediate phase and no significant change in urinary output volumes. This is seen in patients with immediate, extensive damage to the hypothalamus. After previously formed ADH has been used up, there is no recovery of borderline viable cells to produce ADH and modify the postoperative course.

The several patterns of expression of clinical DI mentioned above should be kept in mind when formulating a postoperative treatment plan. Therapeutic regimens need to be flexible, because the degree and duration of the disease process are uncertain.

Patients with significant preoperative DI seldom have any postoperative improvement. In that group of patients it is reasonable to resume preoperative medical treatment as soon as practical.

Patients likely to develop DI after surgery (i.e., those with surgery in and around the hypothalamic and pituitary area) are treated expectantly. Until polyuria becomes apparent, the patient is treated with standard parenteral fluid replacement. Urinary output should be monitored closely, with volume readings hourly if the patient has an indwelling bladder catheter, or otherwise as urine specimens are obtained. The body weight should be recorded before surgery and at least once a day in the postoperative period. Patients who are able to take liquids by mouth in the prepolyuria phase are allowed to drink at will, but careful charting of intake and output must continue.

When polyuria appears, treatment is determined primarily by the patient's clinical status, urine volume, and the concentration of the serum electrolytes (especially sodium) and creatinine. A patient who is alert and taking food by mouth may be able to regulate the fluid intake satisfactorily as dictated by thirst, especially if the serum Na+ is 140 meq/litter or less. Body weight and serum electrolytes are measured twice daily. If the urinary output exceeds an average of 250 ml/h for two consecutive hours or 3 to 4 litters per day, or if the patient is unable to maintain adequate intake orally, medication is given. Intervention is indicated if the serum sodium level rises, especially if it exceeds 145 meq/litter. DDAVP, given by a subcutaneous, intravenous, or intranasal route, is the treatment of choice. Aqueous vasopressin, which has, effects at both the V1 (vascular) and V2 receptors, currently has little role in the treatment of DI. Pitressin tannate in oil is no longer manufactured. The most difficult management problem is presented by patients who are unable to maintain adequate oral intake, particularly lethargic or obtunded patients. In the latter group, the clinical parameter of thirst is lost, and meticulous fluid intake and output records become essential. Twice-daily weight records provide a valuable guide to the state of hydration. If fluid intake and output are approximately equal, the patient may maintain weight or occasionally lose a small amount of weight, but will never gain weight. If the urinary output is very large or there is concern about the patient's status, the serum electrolytes, blood urea nitrogen (BUN), and hematocrit are measured twice a day. If the urinary output is relatively low, once-a-day measurement of these indices is adequate. The serum osmolality is best measured directly but can be estimated (within 5 percent) by the following formula if the serum electrolytes, BUN, and blood sugar are known:

Serum osmolality= (2X[Na⁺]) + (serum glucose/18) + (BUN/3)
Note:sodium in meq/litre, glucose in mg/dl and BUN in mg/dl.

When blood sugar and renal function are normal, a reliable estimate is twice the serum sodium value (meq/litter) plus 10. An attempt should be made to equalize fluid intake with fluid output. The equalization can be done at intervals varying from 1 h to 1 day, depending on the degree of polyuria. If the patient has a large urinary output (over 200 ml/h), it is best to maintain fluid balance on an hourly basis; if the urinary output is less than that, it is reasonable to maintain fluid balance on a 4 to 6 h basis.

Because fluid should be replaced as free water, intravenous fluids should consist almost solely of dextrose-in-water solutions, and oral fluids should consist mainly of water, such as tap water. The only electrolyte replacement required in the postoperative period is what would normally be given to a postoperative patient; this should be administered as 1 litter of a balanced electrolyte solution and should not be divided in several infusions.

If salt solutions are used continuously, they deliver a continuing solute load to the kidneys, which will aggravate the renal loss of water. Solute concentration cannot be increased in the absence of ADH. The administration of saline solutions as replacement for the urinary loss in diabetes insipidus is probably the most common error in the management of this problem.

In the awake patient with an intact thirst mechanism, it is possible to replace large urinary outputs by oral intake, particularly if some intravenous supplementation is also used. In the very young or in older patients with associated medical problems, it is preferable to keep fluid intake at lower levels. DDAVP can be used at any time in the postoperative period if there is careful monitoring of fluid balance.

An iatrogenic inappropriate ADH-like syndrome can be created in patients given excess exogenous DDAVP or vasopressin along with excess water by mouth or parenterally. This complication can be avoided through careful management of the fluid balance and monitoring of the serum sodium level. The two most important things to remember in managing acute DI are that the primary problem is water loss and that the process is not static but dynamic. Diabetes insipidus can be a serious disorder and, if not corrected, can lead to death.

Aqueous vasopressin is a sterile solution of synthetic 8-arginine vasopressin available in 0.5- and 1-ml ampoules of 20 IU /ml. The short duration of action of this preparation (4 to 6 h) and its effects on tissues other than the kidney make it unsuitable for prolonged use. In the acute stage a slow, continuous infusion of not more than 3 IU/h or intermittent intramuscular injections of 0.1 to 1.0 ml are usually effective. However, aqueous vasopressin can cause angina in patients with coronary artery disease, as well as nausea and vomiting, through its effects on the splanchnic vasculature.

Desmopressin acetate (DDAVP) is a long-acting analogue of arginine vasopressin. It is provided in an aqueous solution in a 10 ml vial in a concentration of 4.0 µg/ml. The altered chemical structure of DDAVP relative to vasopressin retards its degradation, and it has high antidiuretic-to-pressor potency (2000:1), essentially acting only on the V2 receptors. This agent is now the drug of choice for treating vasopressin-sensitive DI.

DDAVP is about 10 times more effective when given by a subcutaneous or intravenous route than when given by intranasal administration. It is generally administered twice daily by the subcutaneous or intravenous route in doses of 1 to 4 µg (0.25 to 1 ml), which are equivalent to 4 to 16 IU of arginine vasopressin. DDAVP is also available for administration by nasal spray or by rhinal tube. The nasal spray is available in a 5 ml bottle with a spray pump delivering 50 doses of 10 µg each. If a dose other than 10 µg is required, the DDAVP may be delivered through a soft plastic rhinal tube inserted into the nose. The tube has four graduations on it, from 0.05 to 0.2 ml, allowing doses of 5 to 20 µg to be delivered through the nostril. The DDAVP rhinal tube is provided in a 2.5 ml vial with two applicators. The concentration of DDAVP in both spray and rhinal tube is 0.1 mg/ml. Of interest, DDAVP is effective in maintaining homeostasis in mild haemophilia A and in von Willebrand's disease (type I).

Lysine vasopressin nasal spray (Diapid) is a synthetic preparation of vasopressin 8-lysine. It is supplied in a plastic bottle (8 ml) containing 50 USP posterior pituitary pressor units per millilitre. Administration of one or two sprays up each nostril 3 to 4 times a day may produce good control of DI. Each spray delivers approximately 2 ID. This agent is mainly effective in mild cases.

Pitressin tannate in oil was a water-insoluble compound of vasopressin that was obtained from animal sources. It was given intramuscularly and was effective in small doses. This agent had a variable but long duration of action (24 to 72 h). It is no longer manufactured and is of historical interest only.

In recent years it has become clear that a number of drugs may be effective in reducing urine volume when given orally. Among these is chlorpropamide, an oral hypoglycaemic agent that may effectively reduce the polyuria in hypothalamic but not in nephrogenic DI. The drug seems to act by potentiating the antidiuretic effect of low levels of endogenous ADH. It is most effective in mild cases, in which the usual dosage is 50 to 250 mg/day. Antabuse-like symptoms and hypoglycemia occasionally cause problems as side effects of this drug.

Paradoxically, thiazide diuretics are the only effective drugs for the treatment of congenital nephrogenic DI. The presence of vasopressin is not required for action, and the mechanism is probably contraction of the extracellular fluid volume owing to loss of sodium. Hydrochlorothiazide should be used in doses of 50 to 100 mg per day. Potassium supplements may be required. The use of chlorpropamide and hydrochlorothiazide together, often in only small doses, may be effective in neurogenic DI because of a synergistic effect. Furthermore, the thiazide diuretic helps to counteract the hypoglycemia that may be a problem in patients with growth hormone or ACTH deficiency when they are treated with chlorpropamide alone.

Other agents for the treatment of DI include carbamazepine, the antineoplastic agents vincristine and cyclophosphamide, the hypolipidemic agent clofibrate, and the analgesic acetaminophen. All may be effective in mild DI by effecting the release of vasopressin and/or enhancing its effect on the kidney. Carbamazepine, in particular, may potentiate the action of chlorpropamide.

1. Diphenylhydantoin. This commonly used agent suppresses the release of both ADH and insulin. The enhancement of free water clearance seldom leads to a significant enough water diuresis to be clinically important, but occasional severe hyperglycaemic episodes have been reported. This drug should probably not be used in patients with partial or difficult-to-control DI.

2. Glucocorticoids. Glucocorticoid administration frequently leads to the full clinical expression of an underlying ADH deficiency. The DI does not disappear when the doses of glucocorticoids are decreased, although there may be a lessening of severity. The effect of high steroid dosages on patients with trauma affecting the hypothalamus or with surgery in the hypothalamic-pituitary area may, on the contrary, benefit DI by reducing local edema.

3. Thyroid hormone. It should also be pointed out that not only cortisol but also thyroid hormone affects the secretion of ADH. Patients with severe hypothyroidism frequently have hyponatremia due to an "inappropriate ADH-like" syndrome, and thyroid deficiency as well as adrenocortical deficiency may alleviate the severity of concomitant DI.

The existence of SIADH was initially proposed to explain the occurrence of renal salt loss and hyponatremia in patients having neither renal nor adrenal disease. The basis of the syndrome is an overexpansion of extracellular fluid (ECF) resulting from abnormal secretion of ADH. The primary features of SIADH remain those described initially:

1. Hyponatremia with corresponding hypo-osmolality of the serum and extracellular fluid
2. Continued renal excretion of sodium (>20 meq/litter) 3. Absence of fluid volume depletion (serum creatinine and BUN are usually low, in contradistinction to hyponatremia from ECF depletion)
4. Greater osmolality of the urine than is appropriate for the osmolality of the plasma
5. Normal renal and normal adrenocortical function
6. Absence of peripheral edema
7. Hypouricemia

The syndrome is characterized by (1) persistence of the hyponatremia despite the administration of sodium (even if several hundred milliequivalents of sodium per day is infused, nearly all of it is lost in the urine) and (2) an abnormal response to a water load: excess water is retained and not promptly eliminated.

In the broadest classification, SIADH is a form of dilutional hyponatremia, and the sine qua non of the syndrome is increased ECF volume. The size of the increase is usually 3 to 4 litters, so peripheral edema is not present. Because of the expanded extracellular volume, the glomerular filtration rate is increased and the renin-angiotensin-aldosterone mechanism is suppressed, leading to a decrease in the renal reabsorption of sodium. Atrial natriuretic peptide (ANP), a peptide derived from the heart, is increased in SIADH and is of much importance in causing the urinary loss of sodium in the face of hyponatremia that is characteristic of this disorder.

SIADH can occur in a wide variety of CNS disorders, including encephalitis, stroke, head trauma, and brain tumors. It has also been described in pulmonary disorders such as fungal, viral, and bacterial pneumonias. The ADH is secreted from the neurohypophysis but is no longer under its normal regulatory influences. It is not clear whether there is an alteration in osmoreceptor function, whether inappropriate information is being transmitted centrally from peripheral volume receptors, or whether some other situation prevails. In some instances, SIADH may result from the ectopic production of ADH from a tumor such as an oat cell carcinoma of the bronchus. Since surgical stress, morphine, barbiturates, and anesthetics may all stimulate ADH secretion, a transient form of SIADH can occur in the immediate postoperative period.

Symptoms in SIADH are related to hyponatremia, which becomes a problem primarily because of hypo-osmolality. Pseudohyponatremia can be seen in association with conditions such as increased blood glucose, hyperlipidemia, and administration of mannitol; in these cases the effective osmolality of the serum is not reduced.

SIADH usually causes no symptoms until the serum sodium concentration falls below 120 meq/litter, but if there is progressive retention of water with rapid reduction in serum sodium, significant symptoms can appear with a serum sodium concentration of more than 120 meq/litter. Symptoms are often nonspecific and include anorexia, nausea, irritability, and an accentuation of focal neurological deficits if there is underlying structural brain damage. If the serum sodium concentration drops to less than 110 meq/litter, severe neurological dysfunction due to brain edema (hyponatremic encephalopathy) may occur, with areflexia, diffuse muscle weakness, seizures, and stupor. The appearance of symptoms varies greatly from one patient to another and with the rate of development of the hyponatremia. Hyponatremia that develops rapidly (in hours) is much more serious than hyponatremia that develops slowly (in days), since the mechanisms that regulate cell volume may not have time to act before cerebral edema occurs.

The treatment of SIADH is determined by the severity of the symptoms. The basis of all treatment is elimination of excess water and treatment of the underlying disease. In patients with minor symptoms, restriction of fluid intake to about 500 ml/day is adequate. A weight loss of 5 to 10 pounds is generally needed before serum sodium returns to normal. In senile patients or those with behaviour disorders, in whom it is difficult to control oral fluid intake, the use of demeclocycline (600 to 1200 mg/day) or lithium carbonate (600 to 900 mg/day), both of which block the renal tubular response to ADH, can be helpful. Furosemide, a loop diuretic that facilitates free water clearance, may also be useful at (40 to 60 mg/day) along with increased oral salt intake.

If symptoms are acute and severe, the patient's serum osmolality needs to be raised more quickly. Hypertonic saline infusions along with a loop diuretic will expedite the water loss; 1000 ml of 3% NaCl or 500 ml of 5% NaCl is infused over 4 to 6 h. Furosemide, 40 to 60 mg, can be given intravenously at the beginning of the infusion and may be repeated in 3 to 4 h. Mannitol infusion can also be used to accelerate the water loss. These emergency measures are designed to raise the Na + level above 120 meq/litter, at which point more conservative measures should be used.

The rate at which the Na+ should be raised has been somewhat controversial because central pontine myelinolysis (CPM) has occurred when there is rapid correction of hyponatremia. Overcorrection to the point of hypernatremia could be responsible for CPM, rather than the rate of correction. It was recommended that hypertonic saline be administered to the symptomatic hyponatremic patient by an infusion pump, the plan being to raise the Na+ by no more than 1 meq/litter per hour until the patient is alert and seizurefree or the Na+ has risen by a total of 20 meq/litter, whichever comes first. Others suggested that the rate of increase of the Na+ should not be greater than 0.5 meq/litter per hour and 25 meq/litter over 48 h.

The differentiation of SIADH from the hyponatremia seen in salt depletion is straightforward. None of the signs of hypovolemia, such as decreased blood pressure, decreased tissue turgor, and elevated BUN, are present in SIADH. The clinical picture most often confused with SIADH is that of the patient with an isotonic fluid loss, usually due to the administration of diuretics, who is treated with hypotonic fluid replacement. In that case the body will sacrifice the maintenance of tonicity for the sake of preserving volume-really a form of hypotonic dehydration. Once again, it should be stressed that the absence of an increase in extracellular volume precludes a diagnosis of SIADH.