Endocrinologic disorders

Published on 20/03/2015 by admin

Last modified 20/03/2015

Print this page

This article have been viewed 1654 times

CHAPTER 8 Endocrinologic disorders

Endocrine assessment

Assessment of the endocrine system is complex when assessing the system as a whole because it regulates all body functions in conjunction with the nervous system. Focusing on assessment appropriate to critically ill patients, the following principles should be considered:

1. Critical illness initiates the stress response.

2. The stress response increases the metabolic rate.

3. The hypothalamic-pituitary axis (Figure 8-1) regulates the metabolic rate. The thyroid and adrenal glands are extremely stressed by the stimulus of critical illness to maintain the increased metabolic rate, along with meeting the energy demands at the cellular level. Hypofunction of the thyroid and adrenals requires assessment of not only the primary glands, but also the hypothalamus (produces releasing factors) and anterior pituitary (produces stimulating hormones.) The hypothalamic-pituitary-target organ feedback loop must be fully intact to maintain normal metabolism.

4. The stress response markedly increases endogenous glucocorticoids, which increase blood glucose. The pancreas may not be able to produce sufficient insulin to manage the glucose level, resulting in hyperglycemia. Insulin may be required to manage hyperglycemia until the stress of illness resolves. People with diabetes mellitus are always challenged with hyperglycemia, and with additional illness, can experience the crisis states of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS).

5. Under prolonged extreme stress, both the adrenal glands and thyroid may be unable to sustain hormone production to support the stress level. Supplemental glucocorticoids (corticosteroids) and thyroid hormones may be needed.

6. The assessment of the critically ill patient should focus on the signs of failure of the endocrine system to support the stress response. Signs of hypofunction are explained the sections on hyperglycemia, adrenal crisis, and myxedema coma. Patients with adequate function of the pancreas, thyroid, and adrenal glands under normal conditions may not be able to maintain balance when exposed to the stress of critical illness. Those with underlying hypofunction are more likely to experience crises.

7. Hyperthermia and cardiac symptoms can make diagnosis of thyroid storm difficult, as the crisis mimics other cardiac crises and infection. Thyroid storm results from underlying Graves’ disease/hyperthyroidism; not a complication of critical illness.

8. Assessment of the causes of unusual fluid and electrolyte imbalances should include evaluation of posterior pituitary function, in addition to screening for renal dysfunction. Posterior pituitary dysfunction may result in abnormal levels of antidiuretic hormone (ADH) and may be a complication of critical illness, or result from hypothalamic or pituitary disease. Diabetes insipidus (DI ) produces dehydration and Syndrome of Inappropriate ADH (SIADH) produces hyponatremia, which can reach critical states if not properly addressed. Nephrogenic DI results from failure of the kidneys to respond to ADH. The elderly are at higher risk of complications with DI as a result of age-related changes to the thirst mechanism and renal function.

9. Medication noncompliance for management of existing endocrine disease must be assessed. People with lower income are at higher risk of crisis due to inability to purchase medications and teenagers may not practice meticulous management; particularly those with diabetes mellitus. Elders may not take medications appropriately due to lack of understanding or mis-dosing due to deteriorating short-term memory.

Figure 8-1 Endocrine system: hypothalamic-pituitary axis feedback loop.

Acute adrenal insufficiency (adrenal crisis)

Pathophysiology

Acute adrenocortical insufficiency, also known as adrenal crisis and Addisonian crisis, is a life-threatening condition that manifests as shock with profound, refractory hypotension. Severe sepsis with pituitary suppression and steroid withdrawal are the most common causes of acute adrenal insufficiency in critically ill patients. Adrenal crisis also results from acute exacerbation of chronic adrenocortical insufficiency in patients who become stressed by sepsis, surgery, adrenal hemorrhage (septicemia-induced Waterhouse-Friderickson syndrome from meningococcemia), and anticoagulation complications. There are approximately 50 total hormones produced by the adrenal glands, with cortisol and aldosterone being by far the most abundant.

The function of the adrenal cortex is dependent on the hypothalamic-pituitary axis. The normal relationship occurs as the hypothalamus secretes releasing factors, which:

1. Stimulate the pituitary to secrete stimulating hormones (adrenocorticotropic hormone [corticotropin] [ACTH]), which in turn

2. Stimulates the adrenal glands to secrete glucocorticoids (cortisol) and mineralocorticoids (aldosterone), which in turn

3. Facilitates cellular functions throughout the body (metabolism), which in turn

4. Creates signals back to the hypothalamus from the cells to increase or decrease releasing hormones (see Figure 8-1).

If primary adrenal insufficiency is the cause of the crisis, the adrenal glands are the root cause of the problem. Addison disease manifests when the entire adrenal cortex is destroyed, which stops the production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Glucocorticoids are essential hormones produced by the adrenal cortex that help maintain vascular tone and cardiac contractility, facilitate wound healing, and support immunity. Cortisol deficiency intensifies the clinical effects of hypovolemia by promoting a decrease in vascular tone, which is partially related to unopposed endothelial production of nitric oxide, and a decreased vascular response to the catecholamine hormones epinephrine and norepinephrine. Relative hypoglycemia may be present, as the breakdown of stored glycogen is not possible without cortisol. Mineralocorticoid hormones are primary regulators of fluid and electrolyte balance, and when unavailable, patients experience hyponatremia, hypovolemia, hyperkalemia, and metabolic acidosis. Large amounts of sodium and water are excreted in the urine. Severe hypotension, shock, and eventually death may occur without intravenous adrenocortical hormone and fluid replacement. In patients with chronic primary adrenocortical insufficiency or Addison disease, acute crises may be prevented by tripling hormone replacement doses during periods of stress.

Primary adrenal insufficiency is relatively rare, can be acute or chronic, and is most often caused by autoimmmune-mediated, idiopathic atrophy. Other causes include tuberculosis, fungal infection, hemorrhage, congenital adrenal hyperplasia, enzyme inhibitors (e.g., metyrapone), cytotoxic agents (e.g., mitotane), and other diseases infiltrating the adrenal glands.

Secondary adrenal insufficiency is relatively common and caused by a failure of either the pituitary gland or hypothalamic-pituitary axis to provide appropriate signals to the adrenal glands to secrete cortisol. Exogenous glucocorticoids (e.g., hydrocortisone) administered elevate the circulating level and the hypothalamic-pituitary-adrenal axis is no longer functional. The adrenal glands do not receive signals to produce endogenous cortisol because the circulating level remains high while the glucocorticoid therapy continues. When glucocorticoid therapy is abruptly discontinued, the adrenal gland cannot immediately respond and the patient experiences adrenal crisis. Secondary adrenocortical insufficiency also manifests when inflammatory mediators or trauma suppress or damage the hypothalamus or pituitary. Pituitary or other tumors may impair pituitary function or, in rarer cases, produce glucocorticoids, which suppress the hypothalamic-pituitary axis.

In patients with possible pituitary suppression from severe sepsis, glucocorticoid replacement for relative adrenal insufficiency remains controversial. Relative adrenal insufficiency is not readily identified by all practitioners. Patients with pituitary dysfunction generally do not require mineralocorticoid replacement because the release of aldosterone is dependent on release of angiotensin II rather than ACTH from the pituitary.

8-1 RESEARCH BRIEF

Sprung and colleagues published a multicenter, double-blind, randomized clinical trial in 2008. Fifty-two ICUs enrolled 500 patients who were older than 18 years with onset of septic shock within the previous 72 hours (SBP less than 90 mm Hg systolic despite fluids or need for vasopressors for longer than 1 hour). An ACTH 250 μg Stimulation Test was performed on all patients meeting criteria. Nonresponders were those patients whose serum cortisol level rose less than 9 μg/dl after stimulation. All of these patients then received hydrocortisone dosing or placebo. Hydrocortisone was administered in the following pattern of deceleration:

1. 50 mg IV every 6 hours × 5 days

2. 50 mg IV every 12 hours on days 6 to 8

3. 50 mg IV every 24 hours on days 9 to 11 and then stopped

The results were dismal in terms of mortality reduction because there was little difference from placebo. Of note, however, was that the group receiving hydrocortisone spent less time in shock by the prior mentioned definition.

From Sprung CL, Annane D, Keh D, et al: Hydrocortisone therapy for patients in septic shock. N Engl J Med 358(2):111–124, 2008.

Endocrine assessment adrenals

Goal of system assessment:

To evaluate for severe hypotension, refractory to volume and vasopressor administration

History and risk factors

• Extreme emotional or physiologic stress, which increases the need for adrenocortical “stress” hormones to mediate the stress response

• Patients previously receiving glucocorticoids (steroids) who may be abruptly withdrawn from steroids or are not given sufficient steroids to manage additional stress

• Adrenalectomy, hypophysectomy, sepsis, human immunodeficiency (HIV) disease

• Other medications: beta adrenergic blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin release blockers (ARBs), nitrates, aspirin, and other platelet inhibitors

Observation and vital signs: primary (first-degree) and secondary (second-degree) insufficiency

• Refractory, severe hypotension resulting from vascular collapse

• Acute abdomen assessment findings: abdominal pain, distention

• Tachycardia and tachypnea

• Hyperpyrexia, with temperatures often reaching in excess of 105°F

• Cyanosis, confusion; may be comatose

• Relative hypoglycemia: tremors, diaphoresis, tachycardia, tachypnea

Observation and vital signs: primary (first-degree) insufficiency only

• Prominent nausea and vomiting

• Weakness

• Signs of dehydration: poor skin turgor, sunken, soft eyeballs, weight loss

• Bronze hue to the skin secondary to excess production of ACTH

• Hyperkalemia, which may be associated with metabolic acidosis: peaked T waves, widening QRS complex, prolonged PR interval, flattened-to-absent P wave

Screening labwork

For suspected acute adrenal crisis

• Random plasma cortisol level: Drawn prior to initiating hydrocortisone replacement but must be interpreted with caution in critically ill patients, because greater than 90% of circulating cortisol is protein bound. When patients are hypoproteinemic, with serum albumin less than 2.5 g/dl, low values may be gleaned from all cortisol testing in patients who have normal adrenal function. A random plasma cortisol level of greater than 25 mcg/dl excludes both primary and secondary adrenal insufficiency.

• Free cortisol level: Done in the setting of hypoproteinemia to better determine the cortisol level. An abnormal test may require a complete endocrinology assessment when the patient stabilizes.

For noncritical adrenocortical insufficiency

• Corticotropin (ACTH) stimulation test: The goal is to differentiate primary from secondary adrenocortical insufficiency or to assess if the adrenal cortex is capable of producing cortisol. Testing of the hypothalamic-pituitary-adrenal axis using this test can differentiate primary from secondary insufficiency. Baseline plasma cortisol level is drawn immediately prior to ACTH administration.

1. A dose of 250 mcg synthetic ACTH is given IM or IV.

• Low-dose protocol: Doses as low as 1 mcg/kg of ACTH have been used to more closely mimic the amount of normal physiologic ACTH released.

2. Within 15 to 30 minutes of receiving ACTH, the normal adrenal cortex releases two to five times the baseline or basal plasma cortisol level.

3. Thirty or 60 minutes following the ACTH injection, another cortisol level is drawn. If the low-dose protocol was used, only the 30-minute cortisol level is accurate.

4. If evaluating for primary adrenal insufficiency, aldosterone levels are drawn with the cortisol levels. The 30-minute aldosterone level is more accurate than the 60-minute level.

• Adrenal insufficiency is diagnosed when:

• Cortisol level: Does not increase at least a total of 9 mg/dl at 30 or 60 minutes following ACTH administration. Typically will rise to above 20 to 30 mg/dL.

• Aldosterone level (if testing specifically for primary insufficiency): An initial value of less than 5 ng/100 ml that fails to double or increase by at least 4 ng/100 ml at 30 minutes following ACTH administration.

Diagnostic Tests for Acute Adrenal Insufficiency

Test	Purpose	Abnormal Findings
*Noninvasive*
Chest radiograph	Assess for heart size and presence of opportunistic infections (primary)	The chest radiogram may be normal but often reveals a small heart. Stigmata of earlier infection or current evidence of tuberculosis (TB) or fungal infection may be present when this is the cause of Addison disease.
Computed tomography (CT) scan of abdomen	Assess abdominal organs, size, presence of blood (primary)	Abdominal CT scan may be normal but may show bilateral enlargement of the adrenal glands in patients with Addison disease because of TB, fungal infections, adrenal hemorrhage, or infiltrating diseases involving the adrenal glands. In Addison disease due to TB or histoplasmosis, evidence of calcification involving both adrenal glands may be present. In idiopathic autoimmune Addison disease, the adrenal glands usually are atrophic.
*Blood Studies*
Complete blood count (CBC) Hemoglobin (Hgb) Hematocrit (Hct) RBC count (RBCs) WBC count (WBCs)	Assess for anemia, inflammation and infection (primary and secondary)	CBC count may reveal a normocytic normochromic anemia, which, upon initial presentation, may be masked by dehydration and hemoconcentration. Relative lymphocytosis and eosinophilia may be present.
Electrolytes Potassium (K⁺) Sodium (Na⁺)	Assess for abnormalities of aldosterone (primary)	Elevation in K⁺ may cause dysrhythmias; decrease of Na⁺ may indicate fluid retention and/or concomitant heart failure.
Serum glucose	Assess for relative hypoglycemia (primary and secondary)	Hypoglycemia may be present in fasted patients, or it may occur spontaneously. It is caused by the increased peripheral utilization of glucose and increased insulin sensitivity. It is more prominent in children and in patients with secondary adrenocortical insufficiency.
Thyroid-stimulating hormone	Assess for thyroid dysfunction (primary and secondary)	Increased thyroid-stimulating hormone, with or without low thyroxine, with or without associated thyroid autoantibodies, and with or without symptoms of hypothyroidism, may occur in patients with Addison disease and in patients with secondary adrenocortical insufficiency due to isolated ACTH deficiency. These findings may be reversible with cortisol replacement.

Collaborative management

DIAGNOSIS AND MANAGEMENT OF CORTICOSTEROID INSUFFICIENCY IN CRITICALLY ILL PATIENTS

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine.
In 2008, an interdisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate. The goal was to develop a strategic tool for defining and treating critical illness acute adrenal insufficiency.
Treatment	Rationale
Moderate dose of hydrocortisone (200–300 mg/day) for critically ill patients with septic shock.	Six randomized control trials demonstrate significant and greater shock reversal in patients who received hydrocortisone although no difference in mortality.
Moderate dose of hydrocortisone in the management of severe early ARDS (PF ratio <200) instituted before day 14.	Five randomized studies evaluated moderate hydrocortisone administration in ARDS from various origins. Consistent improvement was reported in the PF ratio, inflammatory markers were reduced, and both ventilator days and ICU length of stay were reduced.
In patients with septic shock, intravenous hydrocortisone should be given in a dose of 200 mg/day in four divided doses or as a bolus of 100 mg followed by a continuous infusion at 10 mg/hr (240 mg/day).The optimal initial dosing regimen in patients with early severe ARDS is 1 mg/kg/day methylprednisolone as a continuous infusion.	Multiple clinical trials, both randomized and not, as well as prospective and retrospective of patients in severe sepsis and ARDS.
Glucocorticoid (GC) treatment should be tapered slowly and not stopped abruptly.	Abruptly stopping hydrocortisone will likely result in a rebound of proinﬂammatory mediators, with recurrence of the features of shock (and tissue injury).
Treatment with dexamethasone has previously been suggested in patients with septic shock until an ACTH stimulation test is performed, this approach can no longer be endorsed	Physiologic and pathologic understanding that dexamethasone leads to immediate and prolonged suppression of ACTH.

From Marik PE, Pastores SM, Annane D, et al: Crit Care Med 36(6):1937–1949, 2008.

Care priorities

1. Correct hypovolemia

Initiate replacement of intravascular fluid volume. Rapid volume replacement is essential, using normal saline crystalloid IV solution. Administer 1 L over the first hour, followed by an additional 1 to 2 L over the next 6 to 8 hours. If hypovolemia persists, colloid/volume-expanding IV solutions may be necessary.

2. Manage hypotension

Use vasopressors if intravascular volume replacement fails to effectively increase BP (see Appendix 6). Response to catecholamine infusions (epinephrine, norepinephrine, dopamine) is reduced in adrenal insufficiency; higher-than-normal doses may be needed to manage refractory hypotension.

3. Replace cortisol

During stressful situations, the normal adrenal gland output of cortisol is approximately 250 to 300 mg over 24 hours. IV hydrocortisone should be given only to adult septic shock patients after it has been confirmed their BP is poorly responsive to fluid resuscitation and vasopressor therapy.

• Administer 100 mg of hydrocortisone in 100 ml of normal saline solution by continuous IV infusion at a rate of 12 ml/hr. Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus.

• A continuous infusion method maintains plasma cortisol levels effectively if the stress level is steady or constant, particularly in patients who rapidly metabolize the drug. Rapid metabolizers have a greater likelihood of having low plasma cortisol levels between IV boluses.

• An alternative method of hydrocortisone administration is 50-75 mg IV every 4-6 hours for 5 days.

• Improvement in BP and other vital signs should be evident within 4 to 6 hours of hydrocortisone infusion. If not, the diagnosis of adrenal insufficiency is questionable.

• After 2 to 3 days, the stress hydrocortisone dose should be reduced to 100 to 150 mg, infused over a 24-hour period regardless of the patient’s status. In addition to helping with adrenal recovery, lower doses may help abate gastrointestinal (GI) bleeding.

• As the patient improves and the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the following 4 to 5 days to daily replacement doses of approximately 3 mg/hr (72 to 75 mg over 24 hours) and eventually to daily oral replacement doses when oral intake is possible.

• If the patient receives at least 100 mg of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary, because the mineralocorticoid activity of hydrocortisone in this dosage is sufficient.

• As the hydrocortisone dose continues to be weaned, mineralocorticoid replacement should begin in doses equivalent to the daily adrenal gland aldosterone output of 0.05 to 0.1 mg daily or every other day.

4. Maintain normal blood glucose level:

If patient is initially hypoglycemic, 50% dextrose may be needed to correct hypoglycemia. When hydrocortisone or other cortisol replacement is initiated, hyperglycemia may result. An insulin infusion may be needed to control the blood glucose (see Hyperglycemia,p 711).

The need for aggressive insulin titration is reduced if the patient is managed using a continuous (24-hour) infusion of cortisol replacement rather than bolus doses every 6 hours.

CARE PLANS FOR ADRENAL INSUFFICIENCY

Deficient fluid volume

Goals/outcomes

Within 12 hours of initiating treatment, patient is moving toward normovolemia as evidenced by BP approaching normal range; heart rate (HR) 60 to 100 beats/min (bpm); respiratory rate (RR) 12 to 20 breaths/min with normal pattern and depth, or if on the ventilator, weaning from the ventilator; central venous pressure (CVP) 2 to 6 mm Hg; if hemodynamic monitoring is in place, pulmonary artery wedge pressure (PAWP) approaching 6 to 12 mm Hg; normal sinus rhythm on electrocardiogram (ECG); and improvement in level of consciousness (LOC).

Fluid Balance

Fluid and electrolyte management

1. Monitor vital signs and hemodynamic measurements every 15 minutes until stabilized for 1 hour. Consult physician or midlevel practitioner promptly for deterioration in vital signs or hemodynamics.

2. Administer IV fluids to replace fluid volume. Initially, rapid fluid replacement is essential.

3. Maintain accurate input and output (I&O) record. Weigh patient daily.

4. Monitor for electrolyte imbalance. Imbalances associated with adrenal insufficiency include the following:

• Hyponatremia: Headache, malaise, muscle weakness, abdominal cramps

• Hyperkalemia: Lethargy, nausea, hyperactive bowel sounds with diarrhea, numbness or tingling in extremities, muscle weakness. Be aware hyperkalemia will worsen in the presence of metabolic acidosis.

5. Monitor ECG continuously; observe for potassium-related changes. Increased ventricular irritability may signal hypokalemia. (See Fluid and Electrolyte Disturbances, Hypokalemia, p 52.)

6. Monitor laboratory results. With appropriate treatment, serum sodium levels should rise to normal and serum potassium levels should fall to normal. Prevent rapid correction or overcorrection of hyponatremia. Serum sodium levels should not be allowed to increase greater than 12 mEq/L during the first 24 hours of treatment because of the risk of neurologic damage. (See Fluid and Electrolyte Disturbances, Hyponatremia, p 46, or Syndrome of Inappropriate ADH, p 734.)

7. Assess mental and respiratory status at frequent intervals. Institute safety measures as indicated. Reorient and reassure patient as needed.

8. Encourage oral fluid intake as patient’s condition stabilizes. Add sodium-rich foods (see Box 8-1) as tolerated. Begin oral glucocorticoid replacement therapy as prescribed.

9. Consult physician or midlevel practitioner if signs and symptoms of fluid and/or electrolyte imbalance persist or worsen.

Box 8-1 PATIENT AND FAMILY EDUCATION CONCERNING GLUCOCORTICOID AND MINERALOCORTICOID REPLACEMENT

Glucocorticoids (e.g., cortisone, acetate, prednisone)

• Take medication in a diurnal pattern to mimic normal secretion (i.e., two thirds of dose in the morning and one third of dose in the afternoon).

• Take steroids with food to decrease gastric irritation.

• Weigh self regularly, and report to physician gains of greater than 2 lb/wk.

• Avoid exposure to infection, and be alert to indicators of infection (e.g., fever, nausea, diarrhea, malaise).

• Contact physician promptly during periods of physical or emotional stress; dosages will require adjustment at these times.

• Indicators of overreplacement: weight gain (moon face, truncal obesity); edema, thin, fragile skin (striae, easy bruising); slow wound healing; chronic fatigue; emotional lability

• Indicators of underreplacement: weight loss, hyperpigmentation, skin creases, anorexia, nausea, abdominal discomfort, chronic fatigue, depression, irritability

Mineralocorticoids (e.g., fludrocortisone, desoxycorticosterone acetate)

• As prescribed, modify diet with liberal amounts of sodium (see Box 1-4), protein, and carbohydrates.

• Weigh self regularly, and report to physician sudden gains or losses greater than 2 lb/wk.

• Contact physician promptly during periods of physical or emotional stress; dosages will require adjustment at these times.

• Indicators of overreplacement: edema, muscle weakness, hypertension

• Indicators of underreplacement: excessive urination, weight loss, decreased skin turgor

Fluid Monitoring; Neurologic Monitoring; Hypovolemia Management; Electrolyte Management: Hyponatremia; Electrolyte Management: Hyperkalemia

Risk for injury

Goals/outcomes

Patient does not manifest symptoms of sepsis; is able to verbalize orientation to time, place, and person, has stable weight, urine output less than 80 to 125 ml/hr, HR 60 to 100 bpm, BP within patient’s normal range, and normothermia.

Immune Status; Infection Status; Energy Conservation

Energy management

1. Monitor and report signs of increasing crisis: urinary output increased from usual amount, changes in LOC, orthostatic hypotension, nausea, vomiting, and tachycardia.

2. Provide a quiet, nonstressful environment. Adjust lighting to meet needs of individual activities, avoiding direct light in the eyes. Control noise when possible. Prevent unnecessary interruptions, and allow for rest periods. Limit the number of visitors and the length of time they spend with patient. Speak softly and reassuringly to patient.

3. Monitor for and manage hyperthermia using tepid baths, antipyretics, and cooling blankets.

4. Maintain a cool environmental temperature. Maintain strict environmental asepsis, and monitor patient carefully for signs of infection. Avoid exposing patient to staff members or visitors who have colds or infections.

Fluid Monitoring; Environmental Management; Infection Protection

Deficient knowledge: illness care

Goals/outcomes

Before discharge from the intensive care unit (ICU), patient understands factors that increase the risk of adrenal crisis, how to avoid adrenal crisis, precautions that must be taken, and when to notify physician or midlevel practitioner.

Knowledge: Disease Process; Knowledge: Energy Conservation; Knowledge: Medication

Teaching: disease process

1. Teach patient about prescribed medications, including purpose, dosage, route of administration, and potential side effects (Box 8-1). Medication administration should mimic normal diurnal pattern of plasma cortisol levels (e.g., two thirds in the morning and one third in late afternoon).

2. Provide dietary instruction: dietary sodium and potassium may need to be adjusted on the basis of the patient’s clinical condition and drug therapy (see discussions of sodium and potassium in Fluid and Electrolyte Disturbances, p. 37).

3. Explain the importance of controlling stress, both emotional and physiologic, which increases adrenal demand. Teach patient to seek medical intervention during times of increased stress (e.g., fever, infection), inasmuch as medication dosages may need to be increased.

4. Teach indicators of overreplacement and underreplacement of steroids, which require prompt medical attention (see Box 8-1).

5. Stress the importance of never abruptly discontinuing use of any steroid preparation. Use must be tapered to avoid precipitation of crisis.

6. Remind patient of the importance of continued medical follow-up.

7. Explain the procedure for obtaining a medical-alert bracelet or card.

Teaching: Prescribed Medication; Emotional Support

Diabetes insipidus

Pathophysiology

Diabetes insipidus (DI) is a metabolic disorder that affects total body free water regulation, resulting in an abnormally high output of extremely dilute urine, increased fluid intake, and constant thirst. The volume of hypotonic urine excreted is 3-20L/day. Vasopressin (antidiuretic hormone [ADH]) is a key component in the regulation of fluid and electrolyte balance, through direct effects on renal water regulation. Vasopressin is produced in the hypothalamus, is stored in the posterior pituitary gland, and exerts action in the kidneys for water regulation. Three subtypes of receptors respond to the effects of vasopressin (Table 8-1).

Table 8-1 LOCATIONS AND ACTIONS OF VASOPRESSIN RECEPTORS

When any aspect of water regulation fails, if free water is lost, the extracellular fluid volume rapidly decreases, causing plasma osmolality and serum sodium to rise. Plasma osmolality is the main determinant of vasopressin secretion from the posterior pituitary. The osmoregulatory systems for thirst and vasopressin secretion, and the actions of ADH on renal water excretion, maintain plasma osmolality between 284 and 295 mOsmol/kg. Thirst and drinking are key processes in the maintenance of fluid and electrolyte balance. Thirst perception and the regulation of water ingestion involve complex neural and neurohormonal pathways. Thirst occurs when plasma osmolality rises above 281 mOsm/kg, similar to the threshold for ADH release. The osmoreceptors regulating thirst are located in the hypothalamus. Situations that alter the balance between plasma osmolality and vasopressin concentration include:

• Rapid changes of plasma osmolality: Rapid increases in plasma osmolality result in an abnormal increase in ADH/vasopressin release.

• Drinking fluids: Oral fluid consumption rapidly suppresses the release of ADH, through afferent pathways originating in the oropharynx.

• Pregnancy: The osmotic threshold for ADH release is lowered in pregnancy.

• Aging: Plasma vasopressin concentrations increase with age, together with enhanced ADH responses to osmotic stimulation. Age-related changes in ADH production can result in blunting of the thirst response, decreased fluid intake, impaired ability to excrete a free water load, and reduced ability of the kidneys to concentrate urine. These changes predispose the elderly to both hypernatremia and hyponatremia.

There are four major subtypes of DI, based on which mechanism involved with concentrating urine has failed:

• Central, hypothalamic or pituitary DI (neurogenic DI) is the most common type and is caused by lack of vasopressin (ADH) production by a diseased or destroyed posterior pituitary gland. Lack of ADH results in massive diuresis, because ADH normally prompts the kidney to concentrate the urine. Approximately 50% of central DI is idiopathic, as diagnostic testing does not reveal a cause. Central DI is usually permanent, but the signs and symptoms (i.e., thirst, drinking fluids, and urination) are controlled by daily use of synthetic vasopressin.

• Nephrogenic DI (NDI) is caused by inability of the kidneys to respond to normal amounts of ADH, resulting from a variety of drugs or kidney diseases including genetic predisposition. The collecting tubules have decreased permeability to water caused by decreased response to vasopressin by the nephrons. NDI does not improve with synthetic vasopressin and may not improve when probable causes are managed. Familial NDI requires lifelong management. Treatments partially relieve the signs and symptoms. Medications, including lithium, amphotericin B, and demeclocycline can induce NDI. Hypercalcemia can sometimes prompt NDI.

• Gestational or gestogenic DI results from a lack of vasopressin that develops during the third trimester of pregnancy if the pregnant woman’s thirst center is abnormal, causing a blunted thirst response, and/or the placenta destroys vasopressin too rapidly. The placenta may increase the action of vasopressinase, the enzyme that breaks down vasopressin. The condition is controlled using synthetic vasopressin until the DI resolves. Vasopressin can generally be discontinued 4 to 6 weeks after delivery. Signs and symptoms of DI will recur with subsequent pregnancies.

• Dipsogenic DI or primary polydipsia results from vasopressin suppression caused by excessive fluid intake. Primary polydipsia is most often caused by an abnormality in the thirst center of the brain. Unquenchable thirst results in water intoxication. Dipsogenic DI is differentiated from central (pituitary) DI using the water deprivation test. There is no cure for dipsogenic DI at present, but symptoms can be safely relieved. Psychogenic polydipsia is another subtype due to psychosomatic causes that has no treatment that is recognized as consistently effective.

The most common presentation of DI is following head trauma or intracranial surgery. When a person cannot adequately respond to stimulation of the thirst center by drinking fluids, extracellular and intracellular dehydration may result. Electrolyte imbalance, primarily hypernatremia, may produce neurologic symptoms ranging from confusion, restlessness, and irritability to seizures and coma. DI sometimes occurs in brain-dead organ donors and must be managed to effectively preserve organs.

In normal individuals, a more concentrated circulating volume stimulates ADH release through activation of osmoreceptors that monitor serum osmolality. ADH is also released as part of the renin-angiotensin-aldosterone mechanism as a result of hypotension sensed by the juxtomedullary apparatus located outside the glomerulus of the kidney. A 5% to 10% decrease in arterial BP is necessary to increase circulating vasopressin concentrations. Progressive hypotension in healthy individuals results in an exponential increase in plasma ADH via baroreceptor stimulation, while osmoregulated ADH release in response to dehydration is more linear. If the hypothalamus is damaged, production of ADH may not be possible and both the ability to regulate circulating volume and vascular tone may be affected.

In addition to the pharmacologic use of vasopressin in managing DI, exogenous vasopressin also has a role in responding to changes in cardiovascular status and is used as an alternative to epinephrine in resuscitation following cardiac arrest. Exogenous vasopressin administration is used to manage vasodilated shock because ADH is also a potent vasopressor agent with actions mediated through receptors (V₁R) located in vascular smooth muscle cells. Although systemic effects on arterial BP are only seen at high concentrations, ADH is also important in maintaining BP in mild volume depletion.

8-2 RESEARCH BRIEF

Vasopressin is used an alternative to epinephrine management of cardiovascular collapse during cardiopulmonary resuscitation. The authors randomly assigned adults with an out-of-hospital cardiac arrest to receive two injections of either 40 IU of vasopressin or 1 mg of epinephrine, followed by additional treatment with epinephrine if needed. The primary end point was survival to hospital admission, and the secondary end point was survival to hospital discharge. Among 1186 patients, 589 were assigned to receive vasopressin and 597 to receive epinephrine. The two treatment groups had similar clinical profiles. There were no significant differences in the rates of hospital admission between the vasopressin group and the epinephrine group either among patients with ventricular fibrillation. Among patients with asystole, however, vasopressin use was associated with significantly higher rates of hospital admission. Cerebral performance was similar in the two groups. The effects of vasopressin were similar to those of epinephrine in the management of ventricular fibrillation and pulseless electrical activity, but vasopressin was superior to epinephrine in patients with asystole. Vasopressin followed by epinephrine may be more effective than epinephrine alone in the treatment of refractory cardiac arrest.

From Wenzel V, Krismer AC, Arntz HR, Sitter H, et al: A comparison of vasopressin and epinephrine for out of hospital cardiopulmonary resuscitation. N Engl J Med 350(2):105–113, 2004.

Larger pharmacologic doses of vasopressin exert powerful vascular effects in the regulation of regional blood flow. The sensitivity of vascular smooth muscle to the vasoconstrictive effects of ADH varies with each vascular bed and within various parts of each bed. Vasoconstriction of splanchnic, hepatic, and renal vessels occurs at ADH concentrations close to the normal range. Selective actions within the kidney blood vessels lead to redistribution of blood flow from the renal medulla to the cortex. Baroregulated (pressure response) release of vasopressin is a key physiologic mediator in an integrated hemodynamic response to volume depletion.

Endocrine assessment: diabetes insipidus

Test	Purpose	Abnormal Findings
Urine osmolality	Assesses for decreased concentration or dilute urine	Decreased to <200 mOsm/kg; may be higher if volume depletion is present
Urine specific gravity	Assesses for dilute urine	Specific gravity: <1.005 Normal is 1.010–1.025
Serum osmolality	Assesses for concentrated blood/hemoconcentration	Increased to >290 mOsm/kg
Serum sodium	Monitors for hypernatremia	Increased to >147 mEq/L
Plasma ADH level (vasopressin level)	Assesses if vasopressin is elevated or decreased	Central DI: Decreased Nephrogenic DI: Normal or increased Gestational DI: Decreased Dipsogenic DI: Decreased
*Water deprivation test (Miller-Moses Test)* Dehydration should prompt the kidneys to concentrate urine.	To distinguish between the types of DI. Assesses for changes in weight, serum and urine osmolality, and specific gravity when fluid intake is prohibited.	Differentiates psychogenic polydipsia from DI. Central DI and NDI are unaffected by this test.
*ADH (Vasopressin) test* ADH administration will correct the problem if ADH was lacking.	Assesses if the kidneys begin to concentrate urine when ADH is administered. Distinguishes NDI from other types of DI.	Corrects central/neurogenic DI, wherein ADH is lacking. NDI is unaffected by ADH administration, since the problem is unrelated to lack of ADH.
Brain or Pituitary magnetic resonance imaging (MRI)	MRI scan used to identify pituitary lesions that may have caused the DI.	If the patient has the “bright spot” or hyperintense emission from the posterior pituitary gland, the patient likely has primary polydipsia. If the “bright spot” is small or absent, the patient likely has central DI.