Central Diabetes Insipidus

Neurogenic or central diabetes insipidus is characterized by a lack of antidiuretic hormone (ADH) that may result from any injury to the anterior hypothalamus, pituitary stalk, or posterior pituitary gland. In acute critically ill patients, the most common causes of diabetes insipidus are surgery for pituitary tumors, cerebral trauma, intracranial hypertension, and brain death (Box 167-1). Diabetes insipidus also may occur as a complication of bacterial meningitis or encephalitis, vascular aneurysm or thrombosis, drug administration, or alcohol intoxication. Injuries to the hypothalamus most often yield permanent diabetes insipidus because ADH is synthesized in the hypothalamus itself. Injuries to the pituitary stalk and neurohypophysis more commonly cause transient diabetes insipidus, because hypothalamic ADH secretion can be effective even in the absence of anatomic pathways to the normal site of release. Chronic diabetes insipidus in critically ill patients generally results from tumors of the pituitary region and from the sequelae of cerebral trauma.

Clinical Picture

In complete hypothalamic or pituitary injuries, diabetes insipidus generally develops 6 to 24 hours after the injury, because previously released ADH remains circulating this long. Patients with untreated diabetes insipidus usually develop urine outputs of 10 to 15 L/d. When the thirst mechanism is preserved, it is activated as soon as osmolality or volemia decreases. If the patient remains conscious and is given free access to water, he or she may be able to drink large amounts and compensate for the urine losses. In other cases, the large amounts of dilute urine rapidly result in dehydration with hypovolemia and hypotension and in hypernatremia with neurologic deterioration. It is important that diabetes insipidus be recognized and treated rapidly, especially in comatose or uncommunicative patients. In patients with partial diabetes insipidus, the onset of polyuria may be delayed, and the volume of urine may be lower. Nevertheless, if urine is hypo-osmolar and the diabetes insipidus is not treated, dehydration and hypernatremia finally occur and cause symptoms.

Clinical signs of hypernatremia usually appear only when the plasma sodium concentration increases to greater than 155 to 160 mEq/L or plasma osmolality increases to greater than 330 mOsm/kg.⁴ Signs may appear sooner if hypernatremia is associated with other metabolic disorders, particularly with disorders that also increase plasma osmolality. Symptoms mainly include confusion and lethargy. Severe hypernatremia results in coma and sometimes seizures. Acute and severe dehydration and hypernatremia may lead to cerebral shrinkage, sometimes associated with subdural or intraparenchymal hemorrhages.

Clinical signs of dehydration include blood volume depletion and hypotension in the most severe cases. Biological markers of dehydration are usually absent in intensive care unit (ICU) patients with central diabetes insipidus, because the urine loss begins abruptly and commonly reaches more than 1 L/h. The free water deficit can be estimated by the following formula:

The formula assumes that only free water has been lost and that sodium stores are normal. Most often, some sodium has been lost together with additional water, and the total water deficit is even higher than that estimated from the formula. A moderate level of hypernatremia (e.g., 155 mEq) already is associated with a free water deficit of more than 4 L and a total water deficit that may be much higher if sodium has been lost.

Differential Diagnosis

The differential diagnosis of polyuria includes diuretic drug intake, hyperglycemia, fluid overload, and fluid mobilization. The search for diuretic administration should include not only conventional diuretics but also mannitol and iodinated contrast agents. Administration of diuretics may not be evident when these substances have been given before admission to the ICU (e.g., in another hospital before patient transfer; in an ambulance during transfer; or in the operating room during neurosurgery, trauma surgery, or vascular surgery). Preventive administration of furosemide and mannitol is given routinely in some neurosurgical procedures and may result in marked polyuria during and after the operation. Hyperglycemia-induced osmotic diuresis is common, can be suspected from polyuria or from hyperglycemia, and is confirmed or ruled out by the presence or absence of glucosuria. Hypervolemia resulting from fluid overload or unmasked by discontinuation of sustained positive-pressure ventilation may increase urine output to greater than 5 L/day for several days in patients with normal renal function. Mobilization of edema during recovery from disease or surgery also can result in sustained polyuria. In all these conditions, however, urine remains close to isotonic (osmolality ≈300 mOsm/kg). Abundant intake of hypotonic fluid can cause polyuria and urine hypotonicity but does not result in hypernatremia if renal function is normal. The observation of decreased urine output after ADH administration is not diagnostic of diabetes insipidus, because ADH can reduce urine output and increase urine osmolality in all conditions except nephrogenic diabetes insipidus.

Treatment

Management of diabetes insipidus includes two components: (1) reduction of excessive urine output and (2) correction of water deficit (Box 167-2). The polyuria of central diabetes insipidus is treated effectively by vasopressin (ADH) or by its synthetic analog, desmopressin acetate (DDAVP [1-deamino-8-D-arginine vasopressin]).^5–7 As indicated by its multiple names, vasopressin not only has antidiuretic but also vasoconstrictive and oxytocic effects, whereas desmopressin essentially retains the antidiuretic action. The effects of aqueous vasopressin (4-10 units subcutaneously or intramuscularly) on diuresis begin rapidly but last for only a few hours. Vasopressin must be repeated every 4 to 6 hours, and it has been recommended only for diagnostic purposes or in acute conditions (e.g., trauma) in which the diabetes insipidus might be transient. The effects of vasopressin tannate in oil emulsion (2-5 units intramuscularly) last 48 to 96 hours, but the preparation requires close attention to warming and mixing the suspension before injection. Vasopressin tannate was once standard therapy in patients with central diabetes insipidus, but now it has been abandoned in favor of desmopressin. Where still available, vasopressin tannate may be used in patients who are refractory to desmopressin or who experience significant side effects of the drug. Desmopressin has prolonged effects (8-20 hours) and is appropriate for intravenous (IV), subcutaneous, and intranasal routes. Lypressin is another ADH analog that is appropriate for intranasal use, but its effectiveness is limited by its duration of action of only 4 to 6 hours. Desmopressin is known to increase factor VIII and von Willebrand factor levels and is sometimes used for this purpose in patients with coagulation disorders and in surgical procedures associated with significant bleeding; however its efficacy in the absence of von Willebrand syndrome is doubtful. In the ICU and for acute central diabetes insipidus, desmopressin is initially given as 10 to 20 µg intranasally and repeated every 30 to 60 minutes until urine output is reduced to less than 100 mL/h. The initial dose required to maintain a normal urine volume ranges from 10 to 60 µg in most patients. The total appropriate dose is repeated when urine output again increases to greater than 200 mL/h (i.e., after 8-24 hours). The dosage must be reduced if urine output is excessively decreased. Systematic administration is not recommended because most cases of diabetes insipidus seen in ICUs are associated with acute events and may be incomplete or intermittent or both. The subcutaneous route is seldom used, because absorption may be erratic in vasoconstricted patients and an IV line is virtually always available in ICU patients. Desmopressin is injected IV when the intranasal route is not available (i.e., in cases of rhinorrhea and facial trauma). The required initial dose ranges from 2 to 20 µg and is given as repeated 2- to 4-µg boluses.

Vasopressin therapy can be associated with arterial hypertension, myocardial infarction, mesenteric infarction, peripheric ischemia, and uterine cramps. Vasopressin tannate may cause allergic reactions ranging from urticaria to anaphylaxis and sterile abscesses at sites of injection. Desmopressin may interfere with anticoagulant drugs and cause hypercoagulability. When given in excess, all these antidiuretic agents can result in oliguria, hyponatremia, and water intoxication. The severity of diabetes insipidus may vary over time, even in patients with chronic diabetes insipidus, and some patients with chronic diabetes insipidus who are used to drinking large amounts of water may continue to do so even if urine output is limited by a diuretic drug.

Patients with acute diabetes insipidus should receive a sufficient amount of water to match urine output until the polyuria is controlled and to correct the deficit of free water that already exists at the time of diagnosis. If the gastrointestinal system is functional, water can be infused at rates of 1 to 2 L/h through a gastric tube. Otherwise, isotonic dextrose should be infused IV in appropriate amounts (hypotonic dextrose administration can be obtained by infusing equal amounts of water and isotonic dextrose in a central vein, but this procedure has been associated with vascular injuries). Practically, the dedicated gastric or IV infusion rate is adjusted at least hourly to match the urine output of the last equivalent period. Additional water is provided to correct the initial water deficit over a few hours. Plasma electrolytes should be monitored every 4 hours until a normal natremia is restored and stabilized. Blood glucose must be monitored closely and hyperglycemia treated aggressively using IV insulin. Failure to control hyperglycemia may be associated with osmotic diuresis due to glucosuria and superimpose an equivalent of diabetes mellitus on the already present diabetes insipidus.

Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus is characterized by the inability of the renal parenchyma to concentrate urine in response to ADH.^7–9 The disorder is seldom diagnosed in the ICU and is usually more severe when it is congenital. Hereditary forms generally result from mutations to the AVP-2 receptors or AQP-2 water channels. Acquired forms are due to vasopressin resistance of the distal tubule and collecting duct, or to markedly reduced renal concentrating capacity. Most of them are attributed to electrolyte disturbances and lithium therapy, but many other drugs have been implicated. Nephrogenic diabetes insipidus may be treated with a low-sodium, low-protein regimen that reduces the solute load, thiazide diuretics that induce a mild volume depletion and help reduce urine volume to acceptable values, and nonsteroidal antiinflammatory drugs such as indomethacin that inhibit prostaglandin synthesis.

Key Points