24: Hyponatremia and Hypernatremia

CHIEF COMPLAINT

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

As noted in Chapter 1, the first task when evaluating patients is to identify their problem(s). Mr. D’s problems clearly include delirium and marked hyponatremia. While other causes of delirium should be considered, (see Chapter 11 Delirium & Dementia) the hyponatremia clearly requires evaluation because it is severe and thus likely to be causing the delirium.

Hyponatremia is defined as serum sodium concentration < 135 mEq/L and is significant when the concentration is < 130 mEq/L. The differential diagnosis for hyponatremia is long but the diagnostic approach can be easily framed in a few simple steps. These pivotal steps include (1) a quick search for rapid diagnostic clues; (2) a clinical assessment of the patients volume status to limit the differential; (3) in clinically euvolemic patients, a review of the patients urine sodium and response to a saline challenge to unmask subtle hypovolemia (4) in euvolemic patient further tests to distinguish the syndrome of inappropriate antidiuretic hormone (SIADH) from other less common causes of euvolemic hyponatremia; and finally (5) an exploration for the risk factors, associated symptoms, and signs for the diagnoses within each subgroup. Each of these steps is discussed below.

The first step recognizes that a few key clinical and laboratory features occasionally point to very specific diagnoses. Examples of these include thiazide use (suggesting diuretic-induced hyponatremia), recent participation in marathon events (suggesting exercise-associated hyponatremia [EAH]), hyperkalemia (suggesting kidney disease or primary adrenal insufficiency), very low urine osmolality (suggesting psychogenic polydipsia, Ecstasy use, or beer potomania) or markedly elevated blood glucose, or a normal serum osmolality (suggesting hyperglycemia-induced hyponatremia and pseudohyponatremia, respectively). Thus, the first pivotal step in approaching hyponatremia systematically reviews these few variables to search for clues (Figure 24-1).

For many patients, the previously mentioned clues are absent and the second pivotal step evaluates the patient’s clinical volume status in order to determine whether they are clinically hypervolemic, clinically euvolemic, or clinically hypovolemic. This allows the differential diagnosis to be narrowed to that appropriate subset of diagnoses (Figure 24-2). Correct classification of the patient’s volume status requires a review of the history, physical exam findings, and laboratory results. The clinical recognition of hypervolemic patients is very accurate because hyponatremia typically develops in patients with advanced heart failure (HF), cirrhosis, nephrotic syndrome, and chronic kidney disease when the disease is easily recognized. Similarly marked hypovolemia is often readily apparent when hypotension or orthostasis is present. However, hypovolemia may also be subtle. Hypovolemic patients may appear clinically euvolemic. Therefore, the differential diagnosis of patients that appear clinically euvolemic includes both euvolemic and hypovolemic etiologies.

The third pivotal step analyzes the clinically euvolemic group to unmask subtle hypovolemia by analyzing (1) the urine Na⁺ or FeNa⁺ and (2) the response to a small saline challenge (Figure 24-3).

1. Spot urine sodium and Fe_Na+

   1. Since hypovolemia promotes avid sodium reabsorption, hypovolemia is usually associated with a low urinary sodium concentration (< 20–30 mEq/L) and low FeNa⁺(< 0.5%). On the other hand, euvolemic patients do not have a stimulus to reabsorb urine sodium and usually have a higher urinary sodium (> 20–30 mEq/L) and Fe_Na+.

   2. Average urinary sodium in hypovolemic patients: 18.4 mEq/L, compared with 72 mEq/L in euvolemic patients

   3. Urine Na⁺ < 30 mEq/L: 63–80% sensitive for hypovolemia, 72–100% specific, LR+ 2.2-∞, LR– 0.2–0.5

   4. Fe_Na+ may be more sensitive.

      1. FE_Na+ = (U_Na+ × P_Cr)/(P_Na+ × U_Cr)

      2. Compares fraction of sodium excreted to fraction of sodium filtered. In hypovolemic states, the fraction excreted should be low (< 0.5%).

      3. One study reported FeNa⁺ < 0.5% 100% sensitive for hypovolemia, 72% specific, LR+ 3.5, LR- 0

   5. False-negative results (elevated urine sodium or FeNa⁺ in hypovolemic patients) may be seen in hypovolemia secondary to:

      1. Diuretics

      2. Primary adrenal insufficiency in which the hypoaldosteronism directly leads to urinary sodium wasting.

      3. Vomiting with accompanying metabolic alkalosis. The metabolic alkalosis causes an obligatory urinary HCO₃⁻ loss, which is accompanied by sodium. Urine chloride may be low and diagnostic in such cases.

   6. False-positive results (low urine sodium in euvolemic patients) may be seen in certain euvolemic patients.

      1. Psychogenic polydipsia. These patients are euvolemic but usually have low urine sodium concentration due to dilution of the excreted sodium in vast quantities of water.

      2. Some patients with SIADH ingest little sodium causing decreased urinary sodium output.

2. Finally the urine Na⁺ and the Fe_Na+ should not be measured in clinically hypervolemic patients. Hypervolemia in such patients is usually associated with ineffective circulating volume, which promotes avid sodium reabsorption. Obtaining urine sodium measurements in such patients may mislead clinicians into classifying these patients as hypovolemic.

3. The response to a small saline challenge can also be diagnostically useful. In hypovolemic hyponatremia patients, antidiuretic hormone (ADH) is triggered by the hypovolemia and suppressed by volume resuscitation. Therefore, saline challenges can suppress ADH, promote a water diuresis, and cause a rise in the serum sodium. On the other hand, in euvolemic patients ADH is not volume dependent and persists despite the saline challenge. The persistent ADH results in retention of the water contained in the saline whereas the sodium is excreted resulting in a paradoxical fall in the serum sodium with a normal saline challenge.

4. Together the urinary sodium and saline challenge can usually accurately categorize euvolemic and hypovolemic patients (see Figure 24-3). Because normal saline can decrease the serum sodium in patients with SIADH, normal saline should not be used in patients with an initial serum sodium < 120 mEq/L. Consultation is advised.

In euvolemic patients a fourth step is required to distinguish SIADH from less common causes of euvolemic hyponatremia (Figure 24-4). Attending “raves” may suggest Ecstasy use. Maximally dilute urine suggests beer potomania, psychogenic polydipsia, or Ecstasy use and a high thyroid-stimulating hormone (TSH) or low cortisol can suggest hypothyroidism or adrenal insufficiency, respectively. Euvolemic patients without any of the aforementioned diagnoses likely have SIADH.

The final step reviews the diagnoses within the appropriate subset, searching for risk factors and associated symptoms or signs that suggest one of those diseases.

The differential diagnosis of hyponatremia classified by volume status is listed below.

Differential Diagnosis of Hyponatremia

1. Hypervolemia

   1. HF

   2. Cirrhosis

   3. Nephrotic syndrome

   4. Renal failure (glomerular filtration rate [GFR] < 5 mL/min)

2. Euvolemia

   1. Thiazide diuretics

   2. SIADH

      1. Cancers (eg, pancreas, lung)

      2. CNS disease (eg, cerebrovascular accident, trauma, infection, hemorrhage, mass)

      3. Pulmonary diseases (eg, infections, respiratory failure)

      4. Drugs

         • (1) ADH analogues (vasopressin, desmopressin acetate [DDAVP], oxytocin)

         • (2) Chlorpropamide (6–7% of treated patients)

         • (3) Carbamazepine

         • (4) Antidepressants (tricyclics and selective serotonin reuptake inhibitors) and antipsychotics

         • (5) Nonsteroidal antiinflammatory drugs (NSAIDs)

         • (6) Ecstasy (MDMA)

         • (7) Others (cyclophosphamide, vincristine, nicotine, opioids, clofibrate)

   3. Hypothyroidism, severe

   4. Psychogenic polydipsia

   5. Secondary adrenal insufficiency

   6. EAH

   7. Beer potomania

3. Hypovolemia

   1. Thiazide diuretics

   2. Salt and water loss with free water replacement (ie, vomiting or diarrhea)

   3. Primary adrenal insufficiency

Before proceeding, it is useful to briefly review the pathophysiology of hyponatremia. Hyponatremia develops when patients do not excrete their daily ingested excess (or free) water. Free water excretion requires 3 distinct mechanisms: glomerular filtration, a functioning thick ascending loop of Henle (to separate water from solute), and low levels of ADH, which prevent water reabsorption from the tubules into the interstitium. Interference with these 3 mechanisms contributes to hyponatremia (Figure 24-5).

Symptoms of Hyponatremia

The adverse effects and manifestations of hyponatremia depend on its severity and rapidity of development. Acute hyponatremia leaves the serum hypotonic relative to the brain. This osmotic gradient drives water into the brain, resulting in cerebral edema and CNS symptoms. Severe acute hyponatremia may cause brain damage, brainstem herniation, respiratory arrest, and death. Rhabdomyolysis may occur. On the other hand, in chronic hyponatremia (most cases) CNS adaptations occur. Neurons decrease their intracellular osmolality, decreasing the osmotic flux of water into the brain in turn causing less cerebral edema. Although minor symptoms are common in chronic hyponatremia, seizures and herniation are much less frequent. Typically, patients with serum sodium levels > 130 mEq/L are asymptomatic; those with levels from 120 mEq/L to 130 mEq/L may have nausea, vomiting, abdominal symptoms, mild cognitive and gait disturbances. Headache, agitation, and confusion may develop in patients with levels < 125 mEq/L. Levels below 120 mEq/L have been associated with seizures and coma.

The first step in evaluating the patient with hyponatremia is to review the history and physical exam for highly specific results that point to a particular diagnosis (see Figure 24-1). Mr. D’s serum glucose and potassium are normal, ruling out hyponatremia from marked hyperglycemia, and decreasing the likelihood of primary adrenal insufficiency. The urine osmolality is high enough to effectively rule out psychogenic polydipsia, beer potomania, or Ecstasy use (see below). The low serum osmolality confirms true hypo-osmolar hyponatremia ruling out pseudohyponatremia. His serum creatinine is also normal ruling out chronic renal failure. The second key pivotal point in the evaluation of hyponatremia is to ascertain whether Mr. D is clinically hypervolemic, euvolemic, or hypovolemic. Mr. D’s marked peripheral edema clearly indicates that he is hypervolemic. Since he is clinically hypervolemic there is no need to check urinary Na+ or Fe_Na+. The final step in clinically hypervolemic patients explores the differential diagnosis looking for risk factors, associated symptoms and signs of possible diagnoses: HF, nephrotic syndrome, cirrhosis, and renal failure. Of these, cirrhosis seems most likely. The smell of alcohol raises the suspicion of alcohol abuse and liver disease, and the bulging flanks suggest ascites due to cirrhosis. HF is also possible although Mr. D has neither an S₃ gallop nor JVD. Nonetheless, HF should still be considered since neither finding is sensitive enough to rule out HF. Renal failure is effectively ruled out by his normal creatinine. Nephrotic syndrome remains a possibility since we do not have any information yet about proteinuria or the serum albumin level. Table 24-1 lists the differential diagnosis.

Leading Hypothesis: Cirrhosis

Textbook Presentation

See Chapter 17, Edema for a full discussion. Patients with cirrhosis may have ascites, variceal hemorrhage, encephalopathy, jaundice, hypoalbuminemia, coagulopathy, and elevated transaminases.

Disease Highlights

1. Hyponatremia is a marker of advanced cirrhosis found in 3% of patients with Child-Pugh class A, 16% in those with class B, and 31% of those with class C.

2. Hyponatremia is associated with a higher frequency of adverse outcomes (including hepatorenal syndrome, hepatic encephalopathy, spontaneous bacterial peritonitis, and death), especially if there is no clear precipitant.

   1. One study of hospitalized patients reported a 25% mortality among cirrhotic patients without hyponatremia compared with 93% among those with hyponatremia.

   2. Furthermore, greater degrees of hyponatremia are associated with an increasing risk of the hepatorenal syndrome and hepatic encephalopathy (Table 24-2).

3. Among patients with cirrhosis and ascites, 22% have sodium ≤ 130 mEq/L.

4. Pathogenesis of hyponatremia in cirrhosis

   1. Hypoalbuminemia and splanchnic dilatation decrease effective circulating volume and decrease systemic vascular resistance respectively, leading to decreased mean arterial pressure, resulting in:

      1. Elevated ADH (particularly important)

      2. Decreased GFR

      3. Increased proximal reabsorption of solute causing decreased solute delivery to loop of Henle

      4. The combination of increased ADH, decreased GFR, and decreased solute delivery to the loop of Henle result in free water retention.

   2. NSAIDs may worsen edema by reducing GFR and worsen hyponatremia. NSAIDs also lower renal PGE₂, which normally antagonizes ADH.

5. Hyponatremia may act synergistically with hyperammonemia to increase cerebral edema and encephalopathy.

Evidence-Based Diagnosis

1. No clinical finding is terribly sensitive for cirrhosis, but some are fairly specific.

   1. Jaundice: 28% sensitive, 93% specific; LR+ 4.0, LR– 0.8

   2. Variceal bleeding: 50% sensitive

   3. Ascites: 35% sensitive, 95% specific, LR+ 7, LR– 0.7

   4. Encephalopathy: 16% sensitive, 98% specific, LR+ 8, LR– 0.9

   5. Splenomegaly: 34% sensitive, 90% specific, LR+ 3.4, LR– 0.7

2. However, certain physical exam findings are common in cirrhotic patients with hyponatremia.

   1. Ascites present in 100%

      Ascites is a very sensitive sign of cirrhosis in hyponatremic patients. Its absence effectively rules out cirrhosis in these patients.

   2. Peripheral edema seen in 59%

3. Laboratory studies:

   1. Mean urine sodium 4 mEq/L (measurements made after diuretics have been stopped for 5 days). (Decreased effective circulating volume causes increased renal reabsorption of sodium.)

   2. Patients with HF also occasionally have ascites, which can erroneously suggest cirrhosis. One study found that a serum NT-proBNP distinguished patients with ascites due to HF from patients with ascites due to cirrhosis. 98% of patients with cirrhosis had levels < 1000 pg/mL whereas all HF patients had levels over 1000 pg/mL. Patients with levels over 1000 pg/mL could have both HF and cirrhosis.

Treatment

1. Since the hyponatremia develops gradually, severe symptoms due to the hyponatremia are uncommon. Nonetheless patients with severe neurologic symptoms (coma or seizures) and severe hypernatremia should be treated emergently with hypertonic (3%) normal saline (Table 24-3).

2. Similar to all patients with chronic hyponatremia, careful and frequent sodium measurement should be performed to ensure the hyponatremia is not corrected too rapidly to ensure that osmotic demyelination syndrome does not develop (see below).

3. Therapy has not been shown to improve survival and is not recommended in asymptomatic patients with serum sodium levels ≥ 120 mEq/L.

4. Fluid restriction is recommended particularly in symptomatic patients and those with severe hyponatremia (< 120 mEq/L).

5. Vaptans: The FDA has recommended vaptans not be used in patients with cirrhosis.

Mr. D’s findings point fairly conclusively to hypervolemic hyponatremia secondary to cirrhosis. The prior history of varices and ascites point to portal hypertension while the jaundice, hypoalbuminemia, and increased INR suggest synthetic failure by the liver. HF secondary to an alcoholic cardiomyopathy is still possible. Other causes of hypervolemia hyponatremia, such as nephrotic syndrome, are less likely but possible. Finally, there is no history of thiazide use to suggest diuretic-induced hyponatremia.

Alternative Diagnosis: HF & Hyponatremia

Textbook Presentation

Typically, patients with HF complain of shortness of breath, dyspnea on exertion, fatigue, and orthopnea. (See Chapter 15, Dyspnea for a complete discussion of HF.)

Disease Highlights

1. Patients with HF and hyponatremia have marked increases in both total body sodium and water retention producing edema and volume overload.

2. In hyponatremic HF patients, free water clearance is impaired and water retention exceeds sodium retention (causing the hyponatremia).

3. Free water clearance is impaired in large part secondary to elevated ADH levels. The fall in cardiac output triggers carotid baroreceptors that in turn stimulate ADH release. Free water excretion is also impaired by decreased renal perfusion (which decreases the GFR) and an increase in proximal sodium reabsorption (which limits delivery to the thick ascending limb of the loop of Henle).

4. Hyponatremia is observed in patients with severe HF and is associated with an increased risk of death.

5. Diuretic therapy (particularly thiazides) can worsen the hyponatremia.

Evidence-Based Diagnosis

See HF discussion in Chapter 15, Dyspnea.

Treatment

1. Treatment of underlying HF

   1. Similar to other patients with HF (see Chapter 15, Dyspnea).

   2. Angiotensin-converting enzyme (ACE) inhibitors

      1. Can help restore sodium levels to normal. ACE inhibitors improve cardiac output, decrease ADH secretion, and facilitate free water excretion. They also directly antagonize the effect of ADH on the collecting tubules.

      2. Hyponatremic HF patients usually have activation of the renin angiotensin system and are susceptible to ACE inhibitor–induced hypotension. Therefore, therapy with ACE inhibitors should be initiated at low doses.

   3. Avoid NSAID use, which can decrease prostaglandin-dependent renal blood flow and worsen renal function.

2. Treatment of hyponatremia

   1. Patients with severe symptomatic hyponatremia (comas, seizures) should receive 3% normal saline (see Table 24-3). Furosemide should be given concurrently to prevent volume overload.

   2. Asymptomatic or mildly symptomatic patients

      1. Consider excessive diuresis accompanied by increased thirst and ingestion of excessive free water.

      2. Restrict water intake < 1000 mL/d and add furosemide to volume overloaded patients to facilitate natriuresis and augment free water loss (furosemide decreases renal medullary gradients which augments free water loss).

      3. Vaptans can also be added if free water restriction and furosemide are inadequate (Table 24-4).

      4. The rate of rise of serum sodium should be carefully monitored. Recent recommendations guide the goal and maximal rate of rise for the serum sodium (Table 24-3). Correction that exceeds these limits should be countered with therapy to reduce the serum sodium (Table 24-3).

      5. Discontinue thiazide diuretics.

Alternative Diagnosis: Nephrotic Syndrome

Textbook Presentation

See Chapter 17, Edema for full discussion. Patients typically complain of edema.

Disease Highlights

1. Lesions may be primary and idiopathic (eg, minimal change lesion) or secondary to systemic disease (eg, diabetes mellitus, malignancy).

2. Glomerular lesion leads to albuminuria and hypoalbuminemia.

   1. Hypoalbuminemia decreases oncotic pressures decreasing effective circulating volume.

   2. Decreased effective circulating volume triggers sodium retention (which may be aggravated by renal insufficiency).

   3. The combination of sodium retention and hypoalbuminemia cause edema and hypervolemia.

   4. The ineffective circulating volume can also trigger ADH release, reduce free water clearance, and promote hyponatremia.

   5. Pseudohyponatremia may be seen secondary to marked hypertriglyceridemia.

Evidence-Based Diagnosis

1. Nephrotic syndrome is characterized by urine protein excretion ≥ 3.5 g/d, edema, hypoalbuminemia, and hyperlipidemia.

2. Renal biopsy can help identify certain underlying disease states.

Treatment

1. Free water restriction.

2. Vaptans may be effective in patients with a GFR > 50 mL/min in patients who do not respond adequately to water restriction (see Table 24-4).

Mr. D’s history, physical exam, and laboratory findings clearly point to severe cirrhosis. HF and nephrotic syndrome are effectively ruled out by the echocardiogram and urinalysis. The key therapeutic decision is the rate at which to increase his serum sodium. Several features suggest great care should be given to avoid overcorrection. First, he does not have severe neurologic symptoms (coma or seizures) that would mandate acute and rapid correction. Second, the hyponatremia is likely chronic. Both the chronicity and his liver disease increase his risk for osmotic demyelination syndrome, a potentially fatal neurologic complication that may develop when chronic hyponatremia is corrected too rapidly (Table 24-5). An important aspect of his care is to ensure a safe and gradual return of his serum sodium to normal.

Again, the first step in evaluating the patient with hyponatremia is to review the history, physical exam, and initial lab findings for highly specific clues that point to a particular diagnosis (ie, a history of thiazide use, recent marathon, marked hyperglycemia, unexplained hyperkalemia, a maximally dilute urine or normal serum osmolality) (see Figure 24-1). She reports that her hypertension is treated with amlodipine (a calcium channel blocker) and her blood glucose and potassium are normal, ruling out marked hyperglycemic hyponatremia and making the diagnosis of primary adrenal insufficiency less likely. Although her urine osmolality is not reported, her urine specific gravity is not very low and not suggestive of psychogenic polydipsia. Finally, the serum osmolality is low, confirming true hypo-osmolar hyponatremia and ruling out pseudohyponatremia. The second key pivotal point is to classify Mrs. L’s clinical volume status as hypervolemic, euvolemic, or hypovolemic (see Figure 24-2). A careful exam should search for signs of hypervolemia (edema, JVD, S₃ gallop, crackles, or ascites) and for signs of hypovolemia (hypotension, tachycardia, or orthostatic hypotension).

Mrs. L’s history and exam suggest neither hypervolemia or hypovolemia. Therefore, she is classified as clinically euvolemic.

The third key pivotal step reviews her urine sodium and response to a saline challenge to determine if she is truly euvolemic or has subtle hypovolemia (see Figure 24-3).

The elevated urine sodium argues against hypovolemia and is consistent with the clinical impression that Mrs. L is euvolemic. As noted in the introduction, 1 L normal saline challenge can also be diagnostically useful, since it may distinguish subtle hypovolemia (which may improve with a normal saline challenge) from euvolemia, which may worsen (see above).

Mrs. L’s lab studies and lack of response to saline confirms euvolemic hyponatremia (see Figure 24-3). The final step explores the differential diagnosis for euvolemic hyponatremia (see Figure 24-4). Causes include SIADH (most common), adverse effect of medication, secondary adrenal insufficiency, severe hypothyroidism (TSH > 50 milli-international units/mL), Ecstasy use, psychogenic polydipsia, and beer potomania. Psychogenic polydipsia and beer potomania are ruled out by the high urine osmolality. At this point the leading hypothesis is SIADH. Table 24-6 lists the differential diagnosis. Further history and laboratory studies may help rank the differential diagnosis.

Mrs. L’s history is not particularly diagnostic. Her normal TSH essentially rules out primary hypothyroidism. Her recent cough and tobacco history raises the possibility of SIADH from a lung cancer. Adrenal insufficiency is a potentially life-threatening cause of hyponatremia and should be considered a “must not miss” diagnosis. Although hyperkalemia suggests adrenal insufficiency, a normal potassium does not rule it out.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: SIADH

Textbook Presentation

Patients are often (although not always) elderly, with a chief complaint of falls, weakness, or confusion. Alternatively, mild hyponatremia may be discovered incidentally on serum chemistries.

Disease Highlights

1. Most common cause of hyponatremia

2. Secondary to inappropriate ADH release despite hypotonicity and euvolemia.

3. Patients are clinically euvolemic. Clinically unapparent volume expansion due to water retention leads to urinary sodium loss.

4. Etiologies

   1. Cancer, 15%: Ectopic production by small cell carcinoma of the lung is the most common malignancy but many other cancers can cause SIADH.

   2. Neurologic disease (eg, stroke, hemorrhage, meningitis, tumors or trauma)

   3. Intrathoracic disease (eg, pneumonia, tuberculosis, acute respiratory failure)

   4. Drugs: Carbamazepine (20–30% of patients), Ecstasy, ADH analogues (vasopressin, DDAVP, oxytocin [5% of patients]), chlorpropamide, NSAIDs, antidepressants (tricyclics and selective serotonin reuptake inhibitors), antipsychotics, cyclophosphamide, vincristine, nicotine, opioids, clofibrate, and many other medications

   5. AIDS

      1. SIADH may be secondary to Pneumocystis pneumonia, CNS infections, or cancer.

      2. Hyponatremia may also develop secondary to HIV-related adrenal insufficiency or diarrhea (with free water ingestion).

         Evaluate patients with HIV and hyponatremia for adrenal insufficiency.

   6. Temporal arteritis

   7. Idiopathic

5. Reset osmostat

   1. A variant of SIADH in which ADH control is modulated to maintain serum sodium levels at a lower range than normal. Patients retain ability to excrete water load at a new equilibrium point.

   2. Therefore, hyponatremia is not progressive.

   3. Patients typically have serum sodium levels between 125 mEq/L and 135 mEq/L.

   4. Very dilute urine osmolality may be seen following water load (< 100 mOsm/L).

   5. Etiology is similar to SIADH.

   6. Treatment is directed at the underlying disorder.

Evidence-Based Diagnosis

1. Standard criteria

   1. Effective plasma osmolality < 275 mOsm/L; can be calculated using the following equation: Effective osmolality = (2 × Na⁺) + (Glucose/18)

   2. Urine sodium is typically > 20-30 mEq/L.

   3. Urine osmolality not maximally dilute due to active ADH (urine osmolality > 100 mOsm/L, usually > 300 mOsm/L).

   4. Patients clinically euvolemic and other causes of euvolemic hyponatremia must be excluded (hypothyroidism, psychogenic polydipsia, secondary adrenal insufficiency).

   5. Patients are not using diuretics.

2. Urine sodium

   1. Patients with SIADH are euvolemic.

   2. Since there is no volume stimulus for sodium retention, sodium is usually > 20–30 mEq/L.

   3. However, 13–42% of patients have low urine sodium and low FE_Na due to low sodium intake.

Treatment

1. Determine and treat underlying etiology.

   1. Review medications; consider CT scan of the chest and head.

   2. SIADH often resolves with treatment of the underlying disorder (eg, cancer, infection). When due to cancer, recurrent SIADH suggests cancer recurrence.

2. It is important to note that isotonic saline without furosemide may worsen hyponatremia because the ADH stimulus promotes water retention while the sodium is excreted. Therapeutic options include fluid restriction < 800 mL/d, salt tablets, salt tablets with furosemide, hypertonic 3% saline, and ADH receptor antagonists.

   Normal saline may worsen hyponatremia in patients with SIADH.

   1. Discontinue any medications that may cause SIADH.

   2. Fluid restriction is often used. Of note, it is unlikely to be successful as the sole measure if urinary osmolality is > 500 mOsm/L.

   3. Salt tablets can increase urinary osmolality and facilitate increased water loss.

   4. Furosemide may be a useful adjunct to salt supplementation because it decreases the concentration of solute in the renal medulla, which impairs water retention and thereby facilitates water excretion.

   5. Hypertonic saline (3%) augments water elimination and is effective.

      1. Recommended for patients with severe neurologic symptoms (coma, seizures; Table 24-3)

      2. May be useful for patients with severe hyponatremia who have less severe neurologic symptoms (confusion, lethargy), but care must be used not to exceed recommended rates of correction (Table 24-3) and avoid subsequent osmotic demyelination syndrome (Table 24-5).

         • (1) Careful calculations (Table 24-7) and frequent sodium monitoring should guide therapy.

         • (2) Hypertonic saline may be used with or without furosemide.

   6. ADH receptor antagonists can be used (see Table 24-4).

   7. Demeclocycline diminishes renal sensitivity to ADH but may cause nephrotoxicity and photosensitivity and is rarely used.

Mrs. L’s elevated urine osmolality is consistent with SIADH. It is important to consider the alternative diagnosis before concluding that she in fact has SIADH. If SIADH is confirmed, a search for the underlying cause is appropriate.

Alternative Diagnosis: Adrenal Insufficiency

Textbook Presentation

Patients may have chronic symptoms of fatigue, weight loss, nausea, vomiting, orthostasis, and abdominal pain or acute symptoms, such as a clinical constellation that suggests septic shock (hypotension and fever). Adrenal insufficiency may also cause hypoglycemia. Both primary and secondary adrenal insufficiency may cause hyponatremia.

Disease Highlights

1. Pathophysiology

   1. Adrenal insufficiency may be primary or secondary.

      1. Primary adrenal insufficiency occurs when damage to the adrenal gland results in inadequate cortisol production. ACTH increases because the hypothalamic pituitary axis attempts to compensate for the hypocortisolism.

      2. Secondary adrenal insufficiency develops when damage to the hypothalamic pituitary system results in inadequate corticotropin (ACTH) production thereby producing inadequate adrenal stimulation and hypocortisolism.

   2. Cortisol normally suppresses ADH release. Decreased cortisol causes increased ADH levels and promotes hyponatremia.

   3. Primary adrenal insufficiency

      1. May decrease the synthesis of other adrenal hormones

         • (1) Aldosterone, DHEA, and catecholamine synthesis may be impaired.

         • (2) Aldosterone deficiency results in salt losses and clinical hypovolemia. The hypovolemia may further stimulate ADH release. Finally, the aldosterone deficiency may also cause hyperkalemia.

           Suspect primary adrenal insufficiency in hyponatremic patients with hyperkalemia.

         • (3) DHEA deficiency affects women (but not men due to testicular androgen synthesis). Findings may include decreased libido, decreased axillary and pubic hair, and amenorrhea.

         • (4) Catecholamine synthesis is also usually impaired (except in autoimmune adrenal disease).

   4. Secondary adrenal insufficiency (hypothalamic-pituitary insufficiency)

      1. Results in isolated cortisol deficiency which, in turn, causes elevated ADH levels and hyponatremia.

      2. Aldosterone is primarily under control of the renin angiotensin system and is unaffected so that patients are often euvolemic and do not suffer from hyperkalemia.

      3. Hyponatremia may be precipitated by inter-current illness, leading to inadequate cortisol response; 43% of patients with secondary adrenal insufficiency had superimposed infection when presenting with hyponatremia.

2. Etiology

   1. Etiologies of primary adrenal insufficiency

      1. Autoimmune adrenalitis (80–90% of cases in developed nations)

      2. HIV infection: Up to 20% of patients with HIV have adrenal insufficiency.

      3. Tuberculosis (most common cause in developing nations)

      4. Less common etiologies: Fungal or cytomegalovirus infections, bilateral adrenal hemorrhage (seen in septic shock, meningococcemia, postoperative patients, and in patients taking anticoagulants), infiltration (cancer), inherited disorders and certain drugs (ketoconazole, rifampin, phenytoin, and others)

   2. Etiologies of secondary adrenal insufficiency (hypothalamic-pituitary insufficiency)

      1. Iatrogenic due to corticosteroid therapy

         • (1) Up to 50% of patients taking long-term corticosteroid therapy (ie, > 7.5 mg/d prednisone for > 3 weeks) have adrenal insufficiency

         • (2) Recovery of hypothalamic-pituitary-adrenal axis may take 9–12 months.

      2. Sepsis

      3. Pituitary tumors (30% of patients with a pituitary macroadenoma exhibit adrenal insufficiency)

      4. Less common etiologies: Pituitary infarction, irradiation, autoimmune hypophysitis, traumatic brain injury, HIV, sarcoidosis, hemorrhage, hemochromatosis, empty sella syndrome

         Suspect hypopituitarism as the cause of hyponatremia in any patient with a history of pituitary disease (eg, macroadenoma, infarction, empty sella syndrome).

3. Adrenal crisis

   1. 3% of patients per year

   2. Often secondary to insufficient increases in glucocorticoid during times of stress

Evidence-Based Diagnosis

1. History and physical exam

   1. Acute adrenal insufficiency (adrenal crisis)

      1. Often presents similarly to septic shock with hypotension (90%), abdominal pain (with rigidity or rebound in 22%), vomiting (47%), confusion (42%) and unexplained fever (66%). Patients may also have unexplained hypoglycemia, hyponatremia, and hyperkalemia.

      2. Often precipitated by inter-current stress (myocardial infarction or infection). May occur in patients without known adrenal insufficiency or in those with diagnosed disease who fail to increase glucocorticoid therapy during infection or stress.

      3. Rare in patients with secondary adrenal insufficiency because aldosterone secretion is preserved in such patients.

   2. Chronic adrenal insufficiency

      1. May present with a variety of nonspecific symptoms (eg, fatigue, weakness, weight loss, musculoskeletal pains).

      2. The frequency of presenting symptoms may be overestimated in the literature dominated by very old case series that discovered advanced disease.

      3. Hypotension and hyperpigmentation are seen only in primary adrenal insufficiency.

         • (1) Hypotension occurs due to concomitant aldosterone deficiency and occurs in ≡ 90% of patients with primary adrenal insufficiency.

         • (2) Hyperpigmentation

           • (a) Develops secondary to a compensatory increase in the release of proopiomelanocortin (POMC), the precursor hormone that contains both ACTH and melanocyte-stimulating hormone.

           • (b) Typically develops in exposed areas such as the face, dorsum of hands and knuckles, as well as the palmer creases of interphalangeal joints. There may also be a blue black hyperpigmentation of the buccal mucosa. Patients often appear “tanned.”

           • (c) Older reports suggest hyperpigmentation was invariable in primary adrenal insufficiency. A more recent report found hyperpigmentation in only 18% of such patients.

      4. Other findings in chronic adrenal insufficiency

         • (1) Weakness, tiredness, fatigue: 100%

         • (2) Weight loss and anorexia: 100%

         • (3) Musculoskeletal complaints 94%

           • (a) Myalgia 71%

           • (b) Flexion contractures 55%

           • (c) Back pain 33%

           • (d) Arthralgia 22%

         • (4) Gastrointestinal symptoms

           • (a) Nausea: 86%

           • (b) Vomiting: 75%

           • (c) Diarrhea: 16%

         • (5) Amenorrhea: 25% of women

         • (6) Postural dizziness: 12%

         • (7) Psychiatric manifestations (memory impairment, delirium, depression, and psychosis): 5–50%

         • (8) Vitiligo: 10–20% (another autoimmune phenomenon)

         • (9) Salt craving: 16%

         • (10) Visual field defects may occur in secondary adrenal insufficiency when pituitary tumors compress the optic tracts.

2. Laboratory tests (Figure 24-6)

   1. Morning cortisol levels

      1. Cortisol secretion demonstrates a marked diurnal variation.

      2. Early morning cortisol levels can help establish or refute adrenal insufficiency.

         • (1) Morning levels > 17 mcg/dL rule out adrenal insufficiency.

         • (2) Morning levels between 3 mcg/dL and 17 mcg/dL are nondiagnostic.

         • (3) Morning levels < 3 mcg/dL establish adrenal insufficiency.

           • (a) In such patients, 8 am ACTH measurements differentiate primary from secondary adrenal insufficiency.

           • (b) ACTH is elevated in primary adrenal insufficiency.

           • (c) ACTH is low in adrenal insufficiency secondary to hypothalamic-pituitary dysfunction.

   2. Diagnostic testing in patients with low or borderline cortisol levels. Check 8 am ACTH levels.

      1. Elevated ACTH (suspected primary adrenal insufficiency)

         • (1) ACTH stimulation test is the test of choice. (Cosyntropin is the synthetic agent used.)

           • (a) Can be performed any time of day

           • (b) 250 mcg cosyntropin given IM or IV

           • (c) Serum cortisol measured 30–60 minutes later

           • (d) Level < 18 mcg/dL (500 nmol/L) rules in adrenal insufficiency

           • (e) Sensitivity, 97.5%; specificity, 95%; LR+, 19.5; LR–, 0.026

         • (2) Adrenal imaging with CT scanning is appropriate in patients with an abnormal cosyntropin stimulation test.

         • (3) HIV testing should be considered.

         • (4) Antibodies against 21-hydroxylase are accurate in the diagnosis of autoimmune adrenalitis.

      2. Low ACTH levels: suspected secondary or tertiary (pituitary-hypothalamic) based adrenal insufficiency

         • (1) ACTH stimulation

           • (a) Chronic (> 1 month) secondary or tertiary adrenal insufficiency results in adrenal atrophy and such patients may not respond to exogenous ACTH. They are likely to have low cortisol levels and an abnormal cosyntropin stimulation test.

           • (b) On the other hand, patients with acute secondary adrenal insufficiency (ie, recent pituitary infarction or pituitary surgery) will not yet have adrenal gland atrophy.

             • (i) In such patients, exogenous ACTH will result in an appropriate bump in cortisol. Thus, such patients can have a normal cortisol response in spite of disease (false-negative).

             • (ii) Such patients require tests that challenge the entire hypothalamic-pituitary axis, such as the insulin tolerance test.

             • (iii) However, this is a complex test that requires experience to avoid complications of hypoglycemia. Endocrine consultation is advised.

         • (2) Pituitary MRI is indicated in patients with secondary adrenal insufficiency.

   3. Serum electrolytes are abnormal in many but not all patients with adrenal insufficiency.

      1. Hyponatremia develops in 88% of patients with primary or secondary adrenal insufficiency due to increased ADH levels.

      2. Hyperkalemia develops in 50% of patients with primary adrenal insufficiency due to aldosterone deficiency. It is not seen in patients with isolated glucocorticoid deficiency (secondary adrenal insufficiency).

   4. Urine electrolytes in hyponatremic patients with adrenal insufficiency: Decreased cortisol causes lack of suppression of ADH, leading to increased ADH and laboratory values similar to SIADH (average urinary sodium, 110 mmol/L; average urine osmolality, 399 mOsm/L)

   5. Eosinophilia has been reported in 17% of patients.

   6. Hypoglycemia is rare in adults.

   7. Evaluation of adrenal insufficiency in acutely ill patients in the ICU is complex.

      1. Severe stressors normally elevate cortisol levels so that cosyntropin stimulation tests are unnecessary.

      2. Hypoalbuminemia complicates the interpretation of cortisol results in ICU patients.

         • (1) Many ICU patients have normal free (active) cortisol levels but low total cortisol levels due to low levels of binding proteins.

         • (2) Free cortisol levels are not widely available, and the low total levels give the misimpression of adrenal insufficiency.

3. Patients with proven primary and secondary adrenal insufficiency should be evaluated for the underlying etiology.

4. Patients with autoimmune adrenal insufficiency should be evaluated for other autoimmune endocrinopathies (serum glucose, TSH, B₁₂, calcium and LH in hypogonadal patients).

Treatment

1. Long-term therapy

   1. In both primary and secondary insufficiency, therapy must replace normal corticosteroid output and the dosage must be automatically increased at times of stress to prevent life-threatening adrenal crisis.

   2. Primary adrenal insufficiency

      1. Glucocorticoid

         • (1) Daily dose: 5 mg (prednisone) or 0.5 mg (dexamethasone) once daily at bedtime. Additional medications may affect glucocorticoid metabolism. Drug interactions need to be carefully considered.

         • (2) Prevention of adrenal crisis

           • (a) Strenuous physical activity: Add 5–10 mg hydrocortisone

           • (b) Pregnancy: Doses may need to be increased in the third trimester and in the peripartum period. Endocrine consultation is advised.

           • (c) Hyperthyroidism: Double or triple daily dose

           • (d) Febrile illness or invasive diagnostic procedures: Double or triple daily dose

           • (e) Major surgery or trauma: 50 mg every 8 hours of IV hydrocortisone

           • (f) A medical alert bracelet should be worn to alert caretakers of adrenal insufficiency and the need for stress dosing in emergencies. In addition, patients in remote areas should have injectable glucocorticoids for emergency situations.

      2. Mineralocorticoid

         • (1) 0.05–0.2 mg/d of fludrocortisone

         • (2) Monitor potassium levels as well as BP

      3. DHEA (50 mg/d) can be considered for women with impaired sense of well being despite glucocorticoid and mineralocorticoid replacement.

   3. Secondary adrenal insufficiency: Glucocorticoids as for primary adrenal insufficiency

2. Treatment of adrenal crisis

   1. Hydrocortisone 100 mg IV and then 100 mg IV every 6–8 hours. For patients who are still being evaluated for adrenal insufficiency, dexamethasone is substituted for hydrocortisone because it is not detected by the cortisol assays.

   2. Normal saline (often up to 1 L/h)

   3. Patients should be monitored closely to ensure that over rapid correction of hyponatremia does not develop with steroid therapy. Both glucocorticoids and fluid resuscitation suppresses ADH, promotes a water diuresis and may result in overcorrection.

   4. Patients with fever should be evaluated for infectious etiologies and treated appropriately. It should not be assumed that fever is secondary to adrenal insufficiency.

   5. Endocrinology consultation is advised.

      When adrenal crisis is suspected, blood tests should be drawn for cortisol and ACTH. Treatment should commence immediately and not await laboratory results.

3. In patients with concomitant hypothyroidism, adrenal insufficiency should be corrected prior to the initiation of thyroid replacement (which can worsen symptoms).

Her corticotropin stimulation tests are normal ruling out adrenal insufficiency and as previously noted her TSH was normal ruling out primary hypothyroidism. (Secondary adrenal insufficiency of recent onset is still theoretically possible, but nothing in the history suggests the patient is at risk for pituitary disease.) Therefore, Mrs. L has SIADH. The final step will be to determine the etiology of the SIADH. As noted above, SIADH can result from a variety of pulmonary, neurologic, or malignant causes. Following clinical clues is important. Her recent cough and long history of tobacco use suggests an underlying pulmonary etiology.

Alternative Diagnosis: Diuretic-Induced Hyponatremia

Textbook Presentation

The most common clinical situation is a small elderly woman taking a thiazide diuretic for hypertension. Patients may be asymptomatic or complain of weakness, lethargy, or occasionally confusion due to hyponatremia.

Disease Highlights

1. One of the most common causes of hyponatremia

2. Often associated with more severe hyponatremia than frequently seen due to other etiologies (mean serum sodium, 116 mEq/L)

3. Most commonly seen with thiazide diuretics; rarely seen with loop diuretics

4. More common in patients over 70 years (OR 3.9)

5. 70% of patients are women

6. Hyponatremia can be multifactorial; pathogenesis may vary in different patients.

7. Pathophysiology

   1. Thiazide diuretics interfere with NaCl transport in cortical diluting segments, causing natriuresis and interfering with the generation of free water within the tubule. This limits free water excretion.

   2. The natriuresis results in hypovolemia.

   3. Hypovolemia may increase ADH levels, and interfere with free water clearance.

   4. Hypovolemia also reduces the GFR, which increases proximal sodium reabsorption leading to reduced distal sodium delivery and reduced free water clearance.

   5. In some patients, hyponatremia develops due to a combination of increased water intake coupled with ADH independent water retention. Such patients appear clinically euvolemic.

8. NSAID use may increase the risk of thiazide-induced hyponatremia.

9. Hyponatremia may persist for 1 month after discontinuation of thiazide.

Evidence-Based Diagnosis

1. Clinical dehydration is evident in only 24% of patients.

2. Symptoms included lethargy 49%, dizziness 47%, vomiting 35%, confusion 17%, and seizures 0.9%.

3. Despite volume depletion, urine sodium concentration may be elevated if diuretic action is still present.

Treatment

1. Symptomatic hyponatremia: See Table 24-3

2. Asymptomatic hyponatremia: Stopping the diuretic is usually adequate. Thiazides should not be reinitiated later. Rapid and dangerous hyponatremia often recurs.

3. Hypovolemic patients

   1. Consider careful volume resuscitation with normal saline.

   2. Unlike euvolemic or hypervolemic patients, fluid resuscitation in a hypovolemic patient may suppress ADH. This may result in rapid water losses and an overly rapid and dangerous correction of the serum sodium concentration resulting in osmotic demyelination syndrome (Table 24-5). Serum sodium levels should be monitored closely and electrolyte replacement may need to be terminated (and free water administered) if serum sodium levels or urinary output rise abruptly (see Table 24-3).

Hypothyroidism

Hypothyroidism is reviewed in detail in Chapter 18, Fatigue. This section will focus on hyponatremia in hypothyroidism.

1. Hyponatremia may occur in 10% of patients with hypothyroidism but is rarely symptomatic.

2. Hyponatremia arises in part secondary to ADH release triggered by a decrease in cardiac output.

3. Hyponatremia only typically develops in severe hypothyroidism (TSH > 50 milli-international units/mL). Patients with mild hypothyroidism and hyponatremia should be evaluated for other causes.

Hypovolemic Hyponatremic Syndromes

Textbook Presentation

Hyponatremia may develop in volume-depleted patients if sodium losses (resulting from vomiting, diarrhea, or excessive perspiration) are replaced with free water. Patients may have orthostatic hypotension or dry mucous membranes.

Disease Highlights

1. The primary controller of ADH release is serum osmolality. Hypo-osmolality normally inhibits ADH release leading to free water diuresis.

2. Significant hypovolemia can stimulate ADH release independent of serum osmolality.

3. Free water ingestion in face of elevated ADH levels causes hyponatremia.

4. Typical urine findings include

   1. Decreased urine sodium concentration (< 30 mEq/L)

   2. Decreased FE_Na (< 0.5%)

   3. Increased urine osmolality (> 450 mOsm/L)

   4. Prerenal azotemia (BUN/Cr > 20)

   5. Elevated uric acid

Treatment

1. For mildly symptomatic patients, normal saline can be used (see calculations above).

2. For severely symptomatic patients with coma or seizures, 3% normal saline can be used (Table 24-3).

3. These patients are at particularly high risk for osmotic demyelination syndrome (Table 24-5) because fluid resuscitation will suppress ADH, promote a water diuresis, and cause the serum sodium to rise faster than formulas predict.

4. Frequent monitoring of serum sodium is mandatory and a lowering of the serum sodium may be necessary if the correction rate exceeds recommended limits (Table 24-3).

Exercise-Associated Hyponatremia

Textbook Presentation

Exercise-associated hyponatremia (EAH) usually presents in patients during or within hours of completing an endurance event (marathon). Symptoms range from weakness and nausea to coma, seizures, and death.

Disease Highlights

1. Typically follows prolonged workout and developed in 6-30% of athletes completing marathons, was severe (< 130 mEq/L) in 2%, and critical (< 120 mEq/L) in 0.6%

2. Secondary to a combination of both excessive fluid intake combined in some patients with inappropriate ADH release.

   1. The leading risk factor is weight gain during the event. Hyponatremia developed in 17% of runners who gained > 2 kg during the race, compared with < 2% of runners who gained < 2 kg.

      1. Ingestion of excessive water or carbohydrate sports drinks can both produce EAH. (Carbohydrate sports drinks are still markedly hypotonic compared with plasma.)

      2. Some studies have also reported an increased risk in women, NSAID users, and long race times.

   2. Hyponatremia should suppress ADH. The finding that 44% of runners with EAH did not have maximally dilute urine suggests that SIADH contributes to hyponatremia in some patients.

3. Rapid onset of hyponatremia renders the plasma hypotonic relative to the brain, leading to cerebral edema.

4. Hyponatremia and cerebral edema cause neurologic symptoms, including confusion, headaches, seizures, coma, and death.

5. Noncardiogenic pulmonary edema has been reported in patients with EAH.

Treatment

1. Prevention

   1. Athletes should be advised to weigh themselves before and after exercise, and counseled to avoid excessive weight gain (> 2 kg).

   2. Thirst should be used as a guide to drinking during marathon events rather than fixed, regular, fluid intake.

   3. Sporadic weight checks during endurance events could also detect athletes with significant weight gain at risk for EAH.

2. Treatment

   1. Individuals who collapse or have neurologic symptoms during or following endurance events should be immediately evaluated for EAH (as well as hypernatremia, hyperthermia, hypoglycemia, and myocardial infarction).

   2. Unlike chronic hyponatremia, EAH develops rapidly and does not allow the brain time to adapt to the hypo-osmolarity.

   3. Therefore, brain edema is more likely (and osmotic demyelination syndrome unlikely). A more aggressive treatment approach is therefore safer and recommended to correct the acute hyponatremia in patients with symptomatic EAH.

   4. 3% normal saline is recommended in patients with hyponatremia (≤ 125 mEq/L) and severe symptoms (confusion, seizures, coma). An initial bolus of 100 mL (of 3% normal saline) is recommended. This may be repeated twice if necessary. Hypertonic saline is optional for patients with a serum sodium of 126–130 mEq/L.

   5. Isotonic saline should not be administered because it may worsen the hyponatremia in patients who have elevated ADH levels.

   6. The osmotic demyelination syndrome from over rapid correction of the serum sodium in patients with EAH has not been reported.

Psychogenic Polydipsia

Textbook Presentation

Psychogenic polydipsia typically occurs in patients with a psychiatric history and unexplained hyponatremia. Patients are unaware of or do not usually admit to excessive water intake. (SIADH may also be seen in psychiatric patients.)

Disease Highlights

1. Increased water intake suppresses ADH, which increases free water excretion and the formation of a dilute urine.

2. Water ingestion is triggered by excessive thirst.

3. Hyponatremia develops only when massive water ingestion is sufficient to overcome maximal urinary free water excretion (usually requires > 8–10 L/d fluid intake).

4. Urine osmolality is maximally dilute (≈ 40-100 mOsm/L).

5. Reported in 6–20% of chronically ill, hospitalized psychiatric patients

6. Since volume status is normal, renal excretion of sodium is usually normal. However, spot urine sodium concentration is low due to dilution by massive water intake. The FENa is usually > 1%.

7. Complications are secondary to both hyponatremia and marked polyuria (incontinence, hypocalcemia, hydronephrosis (from massive urinary output), and HF.

8. Surprisingly, not all patients with psychogenic polydipsia have a maximally dilute urine. Several problems can aggravate the hyponatremia in psychogenic polydipsia and complicate the diagnosis.

   1. Psychotic episodes may cause a transient release of ADH or an increased renal responsiveness to ADH.

   2. In addition, psychiatric medications can induce concomitant SIADH (including selective serotonin reuptake inhibitors and phenothiazines). This accentuates the hyponatremia and can produce a higher than expected urine osmolality.

Evidence-Based Diagnosis

1. Water restriction test can prove the diagnosis by demonstrating rapid resolution of hyponatremia.

2. Mean urine sodium concentration is 18 mEq/L.

3. FE_Na > 0.5% in 66%

4. Mean urine osmolality 144 ± 23 mOsm/L vs 500 mOsm/L in SIADH and 539 mOsm/L in hypovolemic patients.

5. CNS tumors may trigger polydipsia and cause hyponatremia. CNS imaging is recommended before making the diagnosis of psychogenic polydipsia.

Treatment

1. For severe neurologic symptoms (eg, seizures, coma), hypertonic saline can be used.

2. Careful free water restriction allows gradual restoration of serum sodium concentration. Over rapid correction should be avoided (see Table 24-3).

Ecstasy (MDMA) Intoxication

Textbook Presentation

Patients are typically college students, attending clubs (raves), who often present on the weekend with anxiety, restlessness, delirium, or seizures.

Disease Highlights

1. MDMA is a synthetic sympathomimetic amphetamine that stimulates the release of norepinephrine, dopamine, and serotonin, and blocks their reuptake.

2. Frequent drug of abuse (up to 5–10% of high school seniors and 39% of US college students have reported use). Its use has been reported in 60–76% of rave participants.

3. Symptoms and signs among emergency department MDMA visits include agitation (38%), anxiety (29%), disorientation (25%), shaking (23%), hypertension (21%), headache (19%), mood changes (19%), psychotic disturbances (17%), loss of consciousness (13%), tachycardia (10%), dilated pupils (10%), hyperthermia (6%).

4. Serious complications among MDMA emergency department visits have included hypoglycemia, hyponatremia, hyperthermia, malignant hypertension, stroke, coma, seizures, myocardial infarction, arrhythmias, nontraumatic rhabdomyolysis, acute kidney injury, liver failure, disseminated intravascular coagulation, and death (even in first time users).

5. Commonly ingested with other drugs

6. Hyponatremia

   1. Discovered in 6% of MDMA-related emergency department visits.

   2. Hyponatremia may be severe and cause cerebral edema, seizures, coma, and death. The mortality in patients with MDMA-induced hyponatremia is 50%.

   3. Secondary to ADH secretion (SIADH) and water intoxication. The water intoxication is prompted by hyperthermia, diaphoresis, and increased thirst. It is further aggravated by “recommendations” to drink large amounts of water.

   4. Unlike other MDMA complications, women are more susceptible to MDMA-induced hyponatremia than men. (85% of the case reports of MDMA-induced hyponatremia have been in women.)

   5. Hyponatremia can occur after just a single dose.

Evidence-Based Diagnosis

1. MDMA is excreted in the urine and can be detected by specific tests.

2. Numerous congeners of MDMA exist.

3. Urine studies may not detect various congeners and the diagnosis is often made clinically.

Treatment

1. The treatment of MDMA intoxication is beyond the scope of this text. Treatment will focus on the hyponatremia.

2. ICU monitoring is usually required.

3. For asymptomatic patients with mild hyponatremia, fluid restriction is usually adequate.

4. For marked symptoms (coma, seizures) in patients with severe hyponatremia (< 120 mEq/L), see Table 24-3.

Pseudohyponatremia

Textbook Presentation

Certain rare conditions interfere with the accurate measurement of sodium and cause the sodium concentration to appear spuriously low. These conditions are referred to as pseudohyponatremia. Causes include marked hyperlipidemia and marked hyperproteinemia. In these conditions, the serum sodium in the plasma phase is actually normal and the measured serum osmolality is normal. However, the measured serum sodium is low because the plasma phase within any aliquot is smaller than normal due to the marked increase in lipid or proteins causing the instrument to calculate a low serum sodium level. These conditions may be suspected in patients with marked hyperproteinemia (ie, patients with multiple myeloma or following immunoglobulin infusions), or marked hyperlipidemia or when there is a significant difference between the measured and calculated serum osmolality. Since the calculated osmolality uses the measured serum sodium level (which is spuriously low), the calculated osmolality is also spuriously low whereas the measured serum osmolality is correct. The difference between the two (the osmolar gap) is elevated. The osmolar gap can be calculated by the following equations:

Marked hyperglycemia works somewhat differently. Marked hyperglycemia draws water into the intravascular space and thereby produces hyponatremia. In this situation, the hyperglycemia makes the serum hyperosmolar. This discussion will be limited to patients with hyponatremia secondary to marked hyperglycemia.

Disease Highlights

1. In poorly controlled diabetes, intravascular glucose acts as an osmotic agent drawing water from the cells into the plasma resulting in hyponatremia.

2. Serum osmolality is elevated (due to the marked hyperglycemia).

3. The elevated serum osmolality stimulates ADH release further accentuating hyponatremia. (Hypernatremia may also occur if water intake is limited. See below.)

4. Correction factors can help predict the serum sodium concentration after the hyperglycemia is treated (and the intravascular water relocates to the intracellular space). The optimal correction factor is controversial.

5. Experiments suggest that the sodium concentration will increase by 2.4 mEq/L for every 100 mg/dL that glucose falls with treatment. A sodium of 129 mEq/L in a patient with a serum glucose of 1000 mg/dL would correct as follows:

   1. Serum glucose will fall 900 mg/dL with treatment (to about 100 mg/dL).

   2. Correct sodium concentration by 2.4 per 100 mg/dL fall in glucose.

   3. 9 × 2.4 = 21.6

   4. Corrected sodium = 129 + 21.6 = 150.6

CHIEF COMPLAINT

As noted in Chapter 1, the first task when evaluating patients is to identify their problem(s). Like hyponatremic patients, hypernatremic patients often suffer from an altered sensorium and serum chemistries reveal hypernatremia. In addition to evaluating other possible causes of confusion, the cause of the hypernatremia should be determined and treatment initiated since the hypernatremia may be contributing to the delirium.

What is the differential diagnosis of hypernatremia? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

Hypernatremia is almost always secondary to a free water deficit. The differential diagnosis of hypernatremia is markedly simpler than that of hyponatremia and usually develops in 1 of 3 situations: (1) impaired water intake, (2) hyperglycemic hyperosmolar state, or rarely (3) diabetes insipidus.

Hypernatremia and hyperosmolality are potent stimulators of thirst, which promotes drinking and protects against hypernatremia. Therefore, hypernatremia occurs almost exclusively in patients who are either unaware of their thirst or physically unable to get to water. The most common clinical scenarios involve infants or debilitated elderly patients with severe dementia. In such patients, normal insensible water losses or increased water loss (ie, from diarrhea) are not matched by oral intake and hypernatremia develops. Normal kidneys respond by maximizing water reabsorption resulting in a high urine osmolality (> 600 mOsm/L). In over 50% of elderly patients, a superimposed process (ie, pneumonia, urinary tract infection, or cerebrovascular accident) is present. The 30-day mortality in elderly hypernatremic patients has been reported at 41.5%.

Clinicians should search for an underlying cause in patients discovered to have hypernatremia.

Hypernatremia may also develop in patients with marked hyperglycemia. The osmotic diuresis results in a free water loss and may result in hypernatremia if free water intake is impaired due to an altered sensorium. This may not be obvious on initial laboratory results because the hyperglycemia draws water from the intracellular compartment into the extracellular compartment diluting the sodium concentration. With treatment of the hyperglycemia, water moves back to the intracellular space and the hypernatremia worsens.

Other causes of hypernatremia are rare and will be touched upon here only briefly. Hypernatremia may develop in patients who have an impairment in renal water conservation (ie, diabetes insipidus). Even in these patients, increased thirst normally prompts increased water intake and allows such patients to compensate and maintain normal sodium levels. (These patients complain of polydipsia and polyuria.) Hypernatremia may develop when a superimposed process limits water intake. The urine osmolality in such patients is inappropriately low (< 600 mOsm/L). Diabetes insipidus can result from pituitary processes that decrease ADH production or renal processes, which cause resistance to ADH. Finally, very rare causes of hypernatremia include hypothalamic lesions, which render patients unaware of thirst despite a normal sensorium, or increased salt intake (ie, infusion of hypertonic saline or salt water ingestion).

In summary the approach to hypernatremia focuses on a thorough history and physical exam with particular emphasis on the assessment of vital signs, orthostasis, and dehydration. A urine osmolality, serum electrolytes, BUN, creatinine, and glucose are often adequate to determine the etiology. Figure 24-7 outlines the approach to hypernatremia.

Differential Diagnosis of Hypernatremia

1. Impaired water intake: urine osmolality > 600 mOsm/L

   1. Neurologic disease (eg, dementia, delirium, coma, stroke)

   2. Water unavailable (ie, desert conditions)

2. Osmotic diuresis with impaired water intake

   1. Hyperosmolar hyperglycemia

   2. Postobstructive diuresis

3. Rare etiologies

   1. Diabetes insipidus (if associated with decreased water intake)

      1. Neurogenic diabetes insipidus (decreased ADH production)

      2. Nephrogenic diabetes insipidus (ADH resistance)

         • (1) Long-term lithium ingestion

         • (2) Hypercalcemia

   2. Hypothalamic lesions causing decreased thirst

   3. Increased salt intake

      1. Salt water ingestion

      2. Hypertonic saline

      3. Isotonic saline replacement of hypotonic saline loss

How reliable is the history and physical exam for detecting hypernatremia?

Signs and symptoms develop due to dehydration (tachycardia, orthostatic hypotension, dry mucous membranes and axilla) and due to the hypernatremia (depressed sensorium, coma, focal deficits, and seizures). Hypernatremia-induced brain shrinkage can also result in rupture of cerebral veins and subarachnoid hemorrhage. Symptoms are more severe when hypernatremia develops rapidly. The clinical findings in patients with hypernatremia are summarized in Table 24-8. No finding was highly sensitive for hypernatremia.

The patient’s underlying dementia put him at increased risk for hypernatremia due to inadequate water intake, particularly if a superimposed illness has resulted in delirium. This is the leading hypothesis. Marked hyperglycemia should always be considered a “must not miss” alternative. Inadequate water conservation due to diabetes insipidus is possible but far less common. Table 24-9 lists the differential diagnosis.

Leading Hypothesis: Hypernatremia Secondary to Inadequate Water Intake

Textbook Presentation

Patients with hypernatremia due to inadequate water ingestion usually have an altered neurologic status or physical disability. A superimposed illness may worsen cognitive function, decrease oral intake, and promote hypernatremia. Mental status is almost always impaired and may vary from confusion to frank coma.

Evidence-Based Diagnosis

The diagnosis is easily confirmed by the presence of hypernatremia, increased urine osmolality, and absence of hyperglycemia.

Treatment

1. The brain adapts to hypernatremia by increasing intracellular osmolality to minimize cellular dehydration.

2. Rapid correction of hypernatremia makes the serum hypotonic relative to the brain. This promotes osmotic movement of water into the brain and cerebral edema. Seizures and death can occur if correction is too rapid.

3. Hypernatremia should be corrected slowly ≅ 0.5 mEq/L/h (≤ 12 mEq/L/d). A reasonable target is 10 mEq/L/d.

4. Calculating infusion rates

   1. Calculate free water deficit = TBW * {(Na_s/140) – 1}.

      1. Na_s is the patient’s serum sodium.

      2. TBW = total body water.

         • (1) In hypernatremic men TBW = 0.5 × weight (kg)

         • (2) In hypernatremic women TBW = 0.4 × weight (kg)

   2. Calculate correction time (days) = (Na_s - 140)/10. Assuming a serum sodium of 160 mEq/L and target sodium of 140, and a reduction rate of 10 mEq/L per day, the correction time (days) = (160 - 140)/10 = 2 days (48 hours)

   3. Calculate infusion rate = free water deficit/correction time

   4. Example: A 70-kg man with a serum sodium of 165 mEq/L

      1. Free water deficit = 35{(165/140)-1} = 6.25 liters

      2. Correction time: (Na_s - 140)/10 = (165 – 140)/10 = 2.5 days or 60 hours

      3. Infusion rate (per hour) of D5W = 6.25L/60 hours = 104 mL/h of D5W

      4. Note that if D5.45NS is used, each liter provides 500 mL of free water. To deliver 6.25 L of free water would require 12.5 L of D5 0.45 NS over 60 hours = 208 mL/h of D5 0.45 NS

      5. Insensible losses should be added, which can be estimated at 30–40 mL/h of D5W. In addition, any other observed ongoing losses (ie, from diarrhea) must be matched.

      6. Online utilities can help with calculations http://www.mdcalc.com/free-water-deficit-in-hypernatremia/

      7. Careful, frequent monitoring of the serum sodium (initially every 4-6h) is required to ensure that correction occurs at a safe rate.

   5. Many such patients are markedly hypovolemic on presentation. Patients who are hypotensive should initially receive normal saline to normalize BP, orthostasis, and urinary output and then be switched to D5W at the appropriate rate to correct the free water deficit.

An elevated urine osmolality can confirm urinary concentrating ability and establish inadequate fluid intake (versus inadequate conservation) as the etiology. An evaluation of the underlying precipitant is also important.

As in the overwhelming majority of cases of hypernatremia, the diagnosis is straightforward. The history, exam, and elevated urine osmolality all confirm hypernatremia due to decreased intake. Urine concentrating ability is intact. Serum glucose is normal. Further diagnostic testing is not required.

Hyperosmolar Hyperglycemic State

See Chapter 12, Diabetes.