hyponatremia. I have a patient with hypernatremia

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hyponatremia. I have a patient with hypernatremia

Scott D. C. Stern, MD

HYPONATREMIA

CHIEF COMPLAINT

PATIENT

Mr. P is a 66-year-old man who comes to the emergency department with a chief complaint of an inability to urinate. Shortly after arrival he has a generalized seizure. Initial labs reveal a serum sodium concentration of 122 mEq/L.

What are the symptoms of hyponatremia? What is the differential diagnosis of hyponatremia? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

As noted in Chapter 1, the first task when evaluating patients is to identify their problem(s). Mr. P’s problems clearly include seizure, marked hyponatremia, and inability to urinate. While other causes of seizures must be considered, the hyponatremia clearly requires evaluation because it is severe, potentially life-threatening, and likely to have caused the seizure.

Hyponatremia is the most common electrolyte abnormality in hospitalized patients and associated with an increase in mortality that is profoundly modified by the underlying cause of hyponatremia. It is defined as a serum sodium concentration < 135 mEq/L and is classified as mild (130–135 mmol/L), moderate (125–129 mmol/L), or profound (< 125 mmol/L).

Symptoms of Hyponatremia

The adverse effects and manifestations of hyponatremia depend on its severity and rapidity of development. Acute hyponatremia (defined as developing within the prior 48 h) leaves the brain hypertonic relative to the hypotonic serum. This osmotic gradient drives water into the brain’s astrocytes, resulting in cerebral edema and CNS symptoms. Acute hyponatremia may cause seizures, brain damage, brainstem herniation, respiratory arrest, rhabdomyolysis and death. Symptoms occur at much more modest degrees of hyponatremia than in patients with chronic hyponatremia. Seizures can occur even at sodium levels above 120 mEq/L. On the other hand, in chronic hyponatremia (most cases), CNS adaptations occur. Astrocytes decrease their intracellular osmolality, decreasing the osmotic flux of water into the brain in turn causing less cerebral edema. Therefore, symptoms tend to develop when hyponatremia is more severe than in patients with acute hyponatremia. Seizures and herniation are much less frequent. Typically, patients with chronic hyponatremia and serum sodium levels > 130 mEq/L are asymptomatic. Symptoms associated with profound hyponatremia (< 125 mEq/L) include nausea (44–49%), vomiting (27–30%), gait disturbance (31%), headache 27%, confusion (14–30%), seizures (5%), and coma.

Before reviewing the differential diagnosis of hyponatremia, it is useful to briefly review the pathophysiology of normal water handling, antidiuretic hormone (ADH), and then hyponatremia. ADH plays a key role in water handling.

In health, dehydration increases the serum sodium and osmolality and triggers ADH release. This causes water channels (aquaporins) to be inserted into the luminal membrane of the collecting ducts, promoting water reabsorption. This restores normal osmolality and sodium concentration. Conversely, excessive water ingestion lowers the serum sodium and osmolality suppressing ADH secretion and results in the removal of the aquaporins. This prevents water reabsorption, promotes its excretion and restores the normal osmolality and sodium concentration.

Hyponatremia occurs when water accumulates in excess of sodium due to an inability to excrete ingested water and in most patients, develops due to an excess of ADH. The excessive ADH release causes persistent, sustained, and inappropriate water reabsorption, diluting the serum sodium (and also simultaneously concentrating the urine). In order to understand the states of increased ADH it is critical to appreciate the triggers of ADH release. ADH is obviously released in response to an increase in osmolality but is also secreted in response to critical hypovolemia (in an attempt to reabsorb water and volume). The hypovolemia can be either real hypovolemia (as in hemorrhagic shock) or perceived hypovolemia, such as when there is an ineffective circulating volume (eg, from severe heart failure [HF]). In addition to these appropriate causes of ADH release, ADH secretion may be inappropriate, causing the syndrome of inappropriate ADH (SIADH). In SIADH, tumors and other diseases cause the release of ADH that is triggered by neither an increase in osmolality nor a decrease in the effective circulating volume. Finally, hyponatremia develops in some patients despite an appropriate suppression of ADH due to the rapid ingestion of such excessive amounts of water that they are unable to excrete it. This is referred to as water intoxication.

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 highly diagnostic clues; (2) a clinical assessment of the patient’s volume status to limit the differential; (3) in clinically euvolemic patients, a review of their urine sodium to detect subtle hypovolemia, and finally, (4) evaluate truly euvolemic patients for hypothyroidism and adrenal insufficiency prior to diagnosing SIADH. Each of these steps is discussed below.

The first step recognizes that a few key clinical and laboratory features immediately suggest very specific diagnoses (Figure 24-1). Examples of these include marked hyperglycemia suggesting hyperglycemic-induced hyponatremia, thiazide use (suggesting diuretic-induced hyponatremia), recent participation in marathon events 406(suggesting exercise-associated hyponatremia [EAH]), hyperkalemia (suggesting kidney failure or primary adrenal insufficiency), very low urine osmolality (suggesting water intoxication from either psychogenic polydipsia, Ecstasy use, or beer potomania), normal serum osmolality (suggesting pseudohyponatremia) or recent attendance at a party, rave etc. (suggesting possible Ecstasy use).

Figure 24-1. Step 1: Look for highly suggestive diagnostic clues.

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, hypovolemic, or euvolemic. 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 their history, physical exam findings, and laboratory results. The clinical recognition of hypervolemic patients is usually straightforward because hyponatremia typically develops in patients with advanced HF, cirrhosis, nephrotic syndrome, and kidney failure when the disease is easily recognized. Conversely, hypotension or orthostasis suggests hypovolemia. Patients who are neither hypervolemic nor hypovolemic are classified as clinically euvolemic.

Figure 24-2. Step 2: Determine the patients clinical volume status.

The third pivotal step evaluates patients who appear clinically euvolemic. Surprisingly, some patients who appear clinically euvolemic are, in fact, hypovolemic. Here, the measurement of the urine sodium can be helpful. Since hypovolemia promotes avid sodium reabsorption within the kidney, hypovolemia is usually associated with a low urinary sodium concentration (< 20–30 mEq/L). 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). Therefore, a low urine sodium in such patients confirms hypovolemia and an elevated urine sodium confirms euvolemia (Figure 24-3).

Figure 24-3. Step 3: Evaluate clinical euvolemia to distinguish true euvolemia from subtle hypovolemia.

There are a few exceptions that should be kept in mind when interpreting the urinary sodium in patients who appear clinically euvolemic.

First, several hypovolemic conditions are associated with an increased urinary sodium loss, which can be misleading. Diuretics can force urinary sodium excretion despite hypovolemia. Therefore, while a low urinary sodium in a patient taking diuretics still suggests hypovolemia, an elevated urine sodium cannot be interpreted. Hypoaldosteronism impairs sodium reabsorption and causes both hypovolemia and increased urinary sodium losses.

Second, several euvolemic states may be associated with low urinary sodium concentrations. Patients with SIADH may ingest little sodium and occasionally have a low urinary sodium measurement (despite euvolemia). Patients with water intoxication (due to psychogenic polydipsia, Ecstasy use, or EAH) may also have a low urinary sodium concentration because the massive water ingestion (and excretion) dilutes the excreted sodium and lowers its concentration. These will usually be identified in the first pivotal step by finding a maximally dilute urine (urine osmolality < 100 mOsm/L).

The final pivotal step evaluates these truly euvolemic hyponatremic patients. Most such patients have SIADH. However, before making this diagnosis, severe hypothyroidism and adrenal insufficiency must be ruled out (Figure 24-4).

Figure 24-4. Step 4: Evaluate euvolemic patients to distinguish SIADH from other diagnoses.

It is important to mention a few potential pitfalls. First, the urine sodium should not be measured in clinically hypervolemic patients. Hypervolemia in such patients is associated with an ineffective circulating volume, which triggers not only ADH release but also promotes avid sodium reabsorption, thereby lowering their urinary sodium. This finding could mislead clinicians into misclassifying these patients as hypovolemic.

Second, a response to a saline challenge is occasionally diagnostically helpful but potentially dangerous. In hypovolemic hyponatremic patients, ADH secretion is triggered by the hypovolemia. The saline challenge can restore the intravascular volume, suppress ADH secretion, and promote a brisk water diuresis. This may cause a dangerously rapid rise in the serum sodium putting patients at risk for developing the osmotic demyelinization syndrome, a severe life-threatening complication of therapy (see below). On the other hand, the opposite can happen in patients with SIADH. In SIADH, ADH secretion continues despite the sodium challenge. This causes the water from the saline to be retained, whereas the sodium is excreted. This can cause a paradoxical fall in the serum sodium from the normal saline challenge, which can worsen CNS symptoms. Consultation is advised.

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

Differential Diagnosis of Hyponatremia

A.  Hypervolemia

1.  HF

1.  Cirrhosis

3.  Nephrotic syndrome

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

B.  Euvolemia

1.  Thiazide diuretics

2.  SIADH

a.  Cancers (eg, pancreas, lung)

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

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

d.  Drugs

(1)  ADH analogs (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 anti-inflammatory 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

C.  Hypovolemia

1.  Thiazide diuretics

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

3.  Primary adrenal insufficiency

Due to Mr. P.’s seizure and subsequent postictal state, Mr. P cannot give a medical history. His chart is requested. Physical exam reveals a man in jogging attire, appearing his stated age. His vital signs are BP, 140/95 mm Hg; pulse, 90 bpm; temperature, 36.0°C; RR, 18 breaths per minute. His neck veins are flat. His lungs are clear to auscultation. Cardiac exam reveals a regular rate and rhythm. There is no jugular venous distention (JVD), S3 gallop, or murmur. His abdomen is obese with no clear mass. No ascites is appreciated. Extremity exam reveals no edema.

At this point, what is the leading hypothesis, what are the active alternatives and is there a must not miss diagnosis?

RANKING THE DIFFERENTIAL DIAGNOSIS

Mr. P’s differential is extensive, but as noted above the first step in evaluating patients with hyponatremia is to review their history and laboratory findings to search for highly specific results that suggest a particular diagnosis. This includes the serum creatinine, glucose, potassium, urine and serum osmolality (Figure 24-1).

Mr. P’s laboratory studies reveal a glucose of 118 mg/dL; K+, 3.9 mEq/L; BUN, 14 mg/dL; creatinine, 0.8 mg/dL; and a serum osmolality of 254 mOsm/L. Urine osmolality is 80 mOsm/L.

Given these laboratory results what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

Mr. P.’s normal serum glucose and creatinine rules out hyponatremia from marked hyperglycemia, and kidney failure, respectively. His normal potassium does not suggest adrenal insufficiency and his low serum osmolality confirms hypotonic hyponatremia ruling out pseudohyponatremia. However, his urine osmolality is exceptionally low and is a pivotal clue. Since ADH (whether appropriate or inappropriate) promotes water reabsorption from the urine, it also acts to increase the urine osmolality. His maximally dilute urine (< 100 mOsm) suggests that ADH is actually suppressed and that the hyponatremia is due to a different mechanism, specifically some form of water intoxication. Causes of water intoxication include psychogenic polydipsia, recent marathon, beer potomania, or Ecstasy use. Given his jogging attire, you suspect EAH. Table 24-1 lists the differential diagnosis.

Table 24-1. Diagnostic hypotheses for Mr. P.

Leading Hypothesis: Exercise-Associated Hyponatremia (EAH)

Textbook Presentation

EAH usually presents in patients during or within hours of completing an endurance event (marathon) who have ingested excessive amounts of free water. Symptoms range from weakness and nausea to coma, seizures, and death.

Disease Highlights

A.  Defined as hyponatremia occurring within 24 hours of physical activity.

B.  Typically follows prolonged workouts of any kind, including half marathons, marathons, ultramarathons, sprint and full ironman events, football players, endurance cycling, and swimming events.

C.  The incidence varies widely. The overall rate of hyponatremia has been reported at 6% of participants, with symptomatic hyponatremia occurring in 1%.

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

1.  The leading risk factor is sustained excessive intake of hypotonic fluid in excess of fluid losses as manifested by 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.

a.  Other risk factors include long exercise duration and slow running pace.

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

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.

E.  The key to understanding EAH is that it develops rapidly unlike most other causes of hyponatremia.

1.  The rapid development causes more severe symptoms at lesser degrees of hyponatremia. Falls in serum sodium of 7–10% can produce symptoms resulting in symptomatic hyponatremia even in patients with sodium levels of 125–130 mEq/L.

2.  The rapid onset of hyponatremia renders the plasma hypotonic relative to the brain, (which still has normal osmolality), leading to an osmotic influx of water into the brain and cerebral edema.

F.  Hyponatremia and cerebral edema cause neurologic symptoms, including confusion, headaches, vomiting, seizures, coma, herniation, and death. Symptoms may not occur immediately but develop over the first 24 hours.

G.  Noncardiogenic pulmonary edema can occur in patients with EAH.

Treatment

A.  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.

B.  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.  It is critical to appreciate that the treatment of acute hyponatremia is different from that of chronic hyponatremia (Table 24-2). The hyponatremia in EAH develops rapidly and an aggressive approach to correction and treatment is safe and recommended. This contrasts with most hyponatremic patients who have chronic hyponatremia, in whom rapid correction can cause a life-threatening complication, the osmotic demyelination syndrome (ODS, see Table 24-3).

Table 24-2. Hyponatremia: approach to treatment.

Table 24-3. Osmotic demyelination syndrome (ODS).

1.  ODS is a life-threatening complication of overly rapid correction of severe chronic hyponatremia (< 120 mEq/L for 2 or more days).

2.  Acute hyponatremia renders the serum sodium hypotonic relative to the astrocytes, causing water influx, astrocyte swelling, and cerebral edema.

3.  In chronic hyponatremia (> 48 hours), the astrocytes in the brain extrude osmols and lower their intracellular osmolality to match the hypotonic serum. This adaptive response causes water efflux and decreases cerebral edema.

4.  Rapid correction of chronic hyponatremia renders the serum hypertonic compared to hypotonic astrocytes, causing water efflux, damaging their cytoskeleton and DNA and potentially causing cell death and demyelination.

5.  The major risk factor for ODS is rapid correction of hyponatremia in patients with marked chronic hyponatremia (virtually always ≤ 120, usually ≤ 105 mEq/L).

6.  Increased risk in patients with hypovolemic hyponatremia, diuretic-associated hyponatremia, treated cortisol deficiency, Na+ < 105 mEq/L, hypokalemia, alcohol abuse, malnutrition, advanced liver disease, and vaptan treatment.

7.  Pons most commonly affected, but other areas of white matter may also be affected.

8.  Develops 2–6 days after correction.

9.  Spastic quadriparesis and pseudobulbar palsy (dysarthria, dysphagia, diplopia), coma, movement disorders, seizures, ataxia, behavioral disorders, and death may occur.

10.  Lesions may not be apparent on MRI for up to 4 weeks after symptoms develop.

11.  Desmopressin and D5W have been used to slow or reverse the rate of rise in serum sodium when it is too rapid.

12.  Desmopressin in conjunction with 3% normal saline has also been used preemptively to prevent a rapid rise in serum sodium in patients at high risk for ODS.

3.  The choice of therapy is guided by the severity of symptoms, not simply the sodium concentration.

a.  Regardless of symptom severity, hypotonic or isotonic saline (normal saline, lactated Ringers) or oral hypotonic fluids are contraindicated because they may worsen the hyponatremia in patients who have elevated ADH levels.

b.  Severe symptoms:

(1)  3% normal saline (hypertonic saline) is recommended in patients with hyponatremia (≤ 125 mEq/L) and severe symptoms (confusion, seizures, coma).

(2)  An initial bolus of 100 mL (of 3% normal saline) is recommended. This may be repeated twice (every 10 minutes) if necessary. Larger single doses may be appropriate when there are signs of impending brainstem herniation (coma, seizures, etc.).

(3)  The 2015 Consensus Guidelines also recommend administering the first dose of 3% normal saline to patients with seizures or coma (following an endurance event) and should not be delayed to confirm hyponatremia.

c.  Mild symptoms:

(1)  Patients with nausea, dizziness, and lightheadedness (but without severe symptoms) can be treated with a either a bolus of hypertonic saline or oral hypertonic saline or observation until the onset of urination.

(2)  Due to the potential for rapid worsening (due to increasing brain edema) continued observation is important.

MAKING A DIAGNOSIS

Mr. P’s brother who accompanied him is questioned and reports that Mr. P never jogs, he just likes wearing jogging clothes. He also says that Mr. P neither drinks nor uses drugs. However, he is unaware of the rest of his medical history.

Have you crossed a diagnostic threshold for the leading hypothesis, EAH? Have you ruled out the active alternatives? Do other tests need to be done to exclude alternative diagnoses?

Clearly the brother’s history makes EAH, beer potomania, and Ecstasy use unlikely. You wonder about the other causes of water intoxication, such as psychogenic polydipsia.

Alternative Diagnosis: Psychogenic Polydipsia

Textbook Presentation

Psychogenic polydipsia typically occurs in patients with a psychiatric history and unexplained hyponatremia. Patients are unaware of (or do not admit) to excessive water intake. Excessive water ingestion and hyponatremia are also seen occasionally in patient who ingest excess water for medical procedures.

Disease Highlights

A.  In most other causes of hyponatremia, ADH is elevated (either appropriately or inappropriately), allowing water to be reabsorbed from the distal tubule, which concentrates the urine. In contradistinction, the increased water intake in psychogenic polydipsia suppresses ADH, increasing free water excretion and results in a dilute urine.

B.  Hyponatremia develops only when massive water ingestion is sufficient to overcome maximal urinary free water excretion and then dilutes the serum sodium, which usually requires > 8–10 L/day fluid intake. (Less water intake can cause hyponatremia in patients with reduced kidney function who are unable to excrete large volumes of free water.)

C.  Therefore, urine osmolality is usually maximally dilute (≈ 40–100 mOsm/L) which is the key to diagnosis.

D.  Reported in 6–20% of chronically ill, hospitalized psychiatric patients. (SIADH may also be seen in psychiatric patients.)

E.  Other causes of voluntary water intoxication include college students (and others) drinking excessive water as a challenge and, rarely, patients who drink water far in excess of what has been medically recommended.

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

Evidence-Based Diagnosis

A.  The water restriction test limits the patient’s access to water. Since water excretion is normal, the patient excretes the excess water promptly and hyponatremia resolves rapidly. However, this must be done carefully in patients with marked hyponatremia (Na ≤ 120 mEq/L) to avoid over-rapid correct of hyponatremia and ODS.

B.  Urine osmolality

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

2.  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.

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

b.  In addition, nausea or 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.

C.  The urine sodium is often low (despite euvolemia) due to the dilution of the sodium in the urine by the massive excretion of water (mean 18 mEq/L). This can incorrectly suggest hypovolemia. However, the fractional excretion of sodium (FENa) is a more accurate measure of volume and sodium handling and is > 0.5% in 66% of patients.

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

Treatment

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

B.  In other patients, careful free water restriction allows gradual restoration of serum sodium concentration. It is worth emphasizing that water restriction is far more effective for patients with water intoxication than for other causes of hyponatremia. Over-rapid correction puts patients at risk for ODS (Table 24-3) and must be avoided.

C.  Table 24-2 summarizes the therapeutic approach to hyponatremia.

CASE RESOLUTION

As Mr. P regains normal consciousness, he reports that he saw blood in his urine 2 days ago and began drinking as much water as possible “gallons and gallons” over the last 36 hours to prevent a clot from forming in his bladder and blocking his urination, (which he feared has happened, given his lower abdominal pain). He denies drinking beer, using any recreational drugs, and any recent endurance activities.

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

Mr. P’s history and low urine osmolality confirm the diagnosis of water intoxication, in this case due to intentional massive water ingestion. An indwelling urinary catheter is placed, allowing bladder flow and over the next 24 hours his spontaneous water diuresis raises his serum sodium to 137 mEq/L! However, since the cause of his hyponatremia was acute (< 48 hours), he was not at risk for ODS (see below). He is educated to limit his water intake.

CHIEF COMPLAINT

PATIENT

Mr. D is a 42-year-old man who is brought to the emergency department by the police department. He is disoriented and confused. Initial labs reveal a serum sodium concentration of 118 mEq/L.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given the differential diagnosis, what tests should be ordered?

Mr. D’s problems clearly include delirium and marked hyponatremia. While other causes of delirium should be considered (see Chapter 11), the hyponatremia clearly requires evaluation because it is severe and thus likely to be causing the delirium.

RANKING THE DIFFERENTIAL DIAGNOSIS

As noted above the first step in evaluating patients with hyponatremia is to review their history and laboratory findings to search for highly specific results that suggest a particular diagnosis. This includes the serum creatinine, glucose, potassium, urine, and serum osmolality (see Figure 24-1).

Due to his confusion, Mr. D cannot give a medical history. His chart is requested. Laboratory studies reveal a glucose of 100 mg/dL; K+, 3.8 mEq/L; BUN, 28 mg/dL; creatinine, 1.0 mg/dL; and a serum osmolality of 252 mOsm/L. Urine osmolality is 480 mOsm/L.

At this point, is the laboratory information sufficient to make a diagnosis? If not, what other information do you need?

RANKING THE DIFFERENTIAL DIAGNOSIS

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 water intoxication (from psychogenic polydipsia, beer potomania, or Ecstasy use). The low serum osmolality confirms true hypo-osmolar hyponatremia ruling out pseudohyponatremia. His serum creatinine is also normal ruling out kidney failure.

As often happens, the initial laboratories studies are not diagnostic. In cases such as this, the second key pivotal point is to ascertain whether Mr. D is clinically hypervolemic, euvolemic, or hypovolemic in order to focus the differential diagnosis (Figure 24-2).

Physical exam reveals a disheveled man appearing older than 42. He smells of alcohol. His vital signs are BP, 90/50 mm Hg; pulse, 90 bpm; temperature, 36.0°C; RR, 18 breaths per minute. He has no orthostatic changes. Neck veins are flat. His lungs are clear to auscultation. Cardiac exam reveals a regular rate and rhythm. There is no JVD, S3 gallop, or murmur. His abdomen is distended, and his flanks are bulging. Extremity exam reveals 3+ pitting edema extending all the way up his thighs.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

Mr. D’s marked peripheral edema clearly indicates that he is hypervolemic. 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 kidney 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 (and HF can also cause ascites). Kidney 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 24-4 lists the differential diagnosis.

Table 24-4. Diagnostic hypotheses for Mr. D.

Review of Mr. D’s past medical record reveals that he has a long history of alcohol-related complications. Six months ago, he was hospitalized for bleeding esophageal varices. There is no history of thiazide use.

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

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

A.  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.

B.  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 of the hyponatremia.

1.  One study of hospitalized patients reported a 25% mortality among cirrhotic patients without hyponatremia compared with 93% among those with hyponatremia. A study of outpatient cirrhotic patients reported a 23% 3-year mortality rate in patients without hyponatremia vs. 53% in those with hyponatremia.

2.  Furthermore, greater degrees of hyponatremia are associated with an increasing risk of the hepatorenal syndrome and hepatic encephalopathy (Table 24-5).

Table 24-5. Comparison of findings in patients who have cirrhosis with and without hyponatremia.

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

D.  Pathogenesis of hyponatremia in cirrhosis

1.  Decreased effective circulating volume (caused by hypoalbuminemia, splanchnic and systemic dilatation) decreases mean arterial pressure, triggering the release of ADH which in turn causes water retention and hyponatremia. Other intrarenal changes also contribute to the hyponatremia.

2.  NSAIDs may decrease the GFR aggravating both edema and hyponatremia. NSAIDs also lower renal PGE2, which normally antagonizes ADH.

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

Evidence-Based Diagnosis

A.  While several physical findings are specific for cirrhosis, none are sufficiently sensitive to rule out cirrhosis in a patient (see Table 17-2).

B.  However, because hyponatremia develops in advanced cirrhosis, 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%

C.  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.  NT-proBNP. Patients with HF also occasionally have ascites, which can erroneously suggest cirrhosis. One study in patients with ascites found that a serum NT-proBNP distinguished HF from 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

A.  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 24-2).

B.  Similar to all patients with chronic hyponatremia, care must be taken to ensure that treatment does not cause the serum sodium to rise too quickly. Rapid correction can cause catastrophic neurologic damage due to ODS (Table 24-3). Table 24-2 lists the current guidelines for the recommended maximum rate of increase in the serum sodium.

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

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

E.  Vaptans (ADH receptor antagonists): The FDA has recommended vaptans not be used in patients with cirrhosis.

MAKING A DIAGNOSIS

Lab studies reveal an albumin of 2.1 g/dL, bilirubin 6.2 mg/dL, AST 85 units/L, ALT 45 units/L, INR of 1.8. An abdominal ultrasound reveals moderate ascites and a small liver with coarse architecture suggestive of cirrhosis.

Have you crossed a diagnostic threshold for the leading hypothesis, cirrhosis? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

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.

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

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

B.  Patients with HF and hyponatremia have marked increases in total body sodium causing volume overload and edema.

C.  In addition, free water clearance is also impaired. Water retention exceeds sodium retention, causing the hyponatremia.

1.  Free water clearance is impaired in large part secondary to elevated ADH levels. This develops when the low cardiac output triggers carotid baroreceptors that stimulate ADH release increasing water reabsorption in the collecting tubules and thereby hyponatremia.

2.  Other factors that contribute to the hyponatremia include a decrease in the GFR (due to decreased renal perfusion) and an increase in proximal sodium reabsorption. (In order to excrete free water, sodium must be delivered more distally, where it can be pumped out of the impermeable parts of the tubule, leaving solute free water behind which can be excreted.)

3.  If used, thiazides diuretics (but not usually loop diuretics) can worsen the hyponatremia.

Evidence-Based Diagnosis

See HF discussion in Chapter 15, Dyspnea.

Treatment

A.  Treatment of underlying HF

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

2.  Angiotensin-converting enzyme (ACE) inhibitors

a.  Can help restore sodium levels to normal. ACE inhibitors (and angiotensin receptor blockers) improve cardiac output, decrease ADH secretion, and facilitate free water excretion. ACE inhibitors also directly antagonize the effect of ADH on the collecting tubules.

b.  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.  Loop diuretics can treat both the hypervolemia and hyponatremia.

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

B.  Treatment of hyponatremia

1.  Patients with severe symptomatic hyponatremia (comas, seizures) should receive 3% normal saline (see Table 24-2). Furosemide should be given concurrently to prevent volume overload.

2.  Loop diuretics as above

3.  Asymptomatic or mildly symptomatic patients

a.  Restrict water intake < 1000 mL/day and add furosemide to volume overloaded patients to facilitate natriuresis and augment free water loss.

b.  ADH receptor antagonists (vaptans) may be an option if free water restriction and furosemide are inadequate (Table 24-6). However, hospitalization and careful monitoring are required to ensure that the correction of serum sodium is not too rapid. Therapy should be limited to < 30 days and avoided in patients with liver disease.

Table 24-6. Vasopressin receptor antagonist (VRA) treatment of hyponatremia.

c.  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 24-2). Correction that exceeds these limits should be countered with therapy to reduce the serum sodium (Table 24-3).

d.  Discontinue thiazide diuretics.

Alternative Diagnosis: Nephrotic Syndrome

Textbook Presentation

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

Disease Highlights

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

B.  Glomerular lesions lead 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 kidney failure).

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 also be seen secondary to marked hypertriglyceridemia.

Evidence-Based Diagnosis

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

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

Treatment

A.  Free water restriction.

B.  Vaptans may be effective in patients with a GFR > 50 mL/min who do not respond adequately to water restriction (see Table 24-6).

CASE RESOLUTION

An echocardiogram reveals normal left ventricular function and a urinalysis reveals only 1+ proteinuria, not suggestive of nephrotic syndrome. A paracentesis is performed to rule out spontaneous bacterial peritonitis and is normal.

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 ODS, a potentially fatal neurologic complication that may develop when chronic hyponatremia is corrected too rapidly (Table 24-3). An important aspect of his care is to ensure a safe and gradual return of his serum sodium to normal.

Mr. D’s mild hyponatremia is corrected slowly. He is begun on free water restriction and his sodium gradually improves to 128 mEq/L. His mental status returns to normal.

CHIEF COMPLAINT

PATIENT

Mrs. L is a 60-year-old woman who comes to see you with a chief complaint of weakness and fatigue. Her past medical history is remarkable only for hypertension that is treated with amlodipine. Routine chemistries reveal a serum sodium of 123 mEq/L. Her potassium and other electrolytes and creatinine are normal. Her glucose is 108 mg/dL and BUN is 28 mg/dL. Follow up labs reveal a serum osmolality is 265 mOsm/L and urine osmolality of 470 mOsm/L.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

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 is not taking a thiazide diuretic, and her blood glucose and potassium are normal, ruling out marked hyperglycemic hyponatremia and making the diagnosis of primary adrenal insufficiency less likely. Her urine osmolality is normal ruling out some form of water intoxication. Her serum creatinine is normal (ruling out kidney failure) and her 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) or hypovolemia (hypotension, tachycardia, or orthostatic hypotension).

Mrs. L denies any history that suggests volume loss (vomiting, diarrhea, or excessive perspiration). She denies symptoms suggestive of hypervolemia such as edema, dyspnea on exertion, or orthopnea. Furthermore, she has no history of any of the diseases associated with hypervolemic states (HF, cirrhosis, kidney disease, or nephrotic syndrome). On physical exam, BP is normal with no significant change going from lying to standing. There is no pretibial or pedal edema. Cardiovascular exam reveals no JVD or S3 gallop. She has no crackles on lung exam, and there are no signs of ascites (bulging flanks, shifting dullness).

Mrs. L’s history and exam suggest neither hypervolemia nor hypovolemia. Therefore, she is classified as clinically euvolemic.

The third key pivotal step reviews her urine sodium to distinguish true euvolemia from subtle hypovolemia (see Figure 24-3).

Mrs. L’s urine sodium concentration is 60 mEq/L.

The elevated urine sodium argues against hypovolemia and is consistent with the clinical impression that Mrs. L is euvolemic. The final step explores the differential diagnosis for euvolemic hyponatremia (see Figure 24-4). Causes include SIADH (most common), secondary adrenal insufficiency, and severe hypothyroidism (thyroid-stimulating hormone [TSH] > 50 milli-international units/mL). Although other disease states can cause euvolemic hyponatremia (such as the water intoxication states and thiazide use), these are usually diagnosed initially by history or a low urine osmolality. At this point the leading hypothesis is SIADH. Table 24-7 lists the differential diagnosis. Further history and laboratory studies may help rank the differential diagnosis.

Table 24-7. Diagnostic hypotheses for Mrs. L.

Past medical history: As noted above, she has hypertension treated with amlodipine. Social history: 40-pack-year history of smoking. Alcohol use is minimal. Mrs. L denies any drug use. Review of systems is unremarkable. Her TSH is 2.3 milli-international units/L (normal < 4.0 milli-international units/L).

Mrs. L’s history is not particularly diagnostic. Her normal TSH essentially rules out primary hypothyroidism. Her recent cough and tobacco history raise 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.

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 elderly, with a chief complaint of falls, weakness, or confusion. Alternatively, mild hyponatremia may be discovered incidentally on serum chemistries.

Disease Highlights

A.  Most common cause of hyponatremia

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

C.  Despite water retention, patients appear clinically euvolemic. Subtle increase in volume leads to urinary sodium loss.

D.  Etiologies: A large variety of diseases may cause SIADH including

1.  Neurologic disease, 9–26%: eg, subarachnoid hemorrhage, stroke, meningitis, tumors, or trauma

2.  Intrathoracic disease, 11–19%: eg, pneumonia, tuberculosis, acute respiratory failure

3.  Cancer, 18–25%: Ectopic production of ADH by small cell carcinoma of the lung is the most common malignancy causing SIADH but many other cancers can cause SIADH.

4.  Postoperative, 7–11%

5.  Drugs, 8–18%: Carbamazepine (20–30% of patients), oxcarbazepine, Ecstasy, ADH analogs (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

6.  AIDS

a.  SIADH may be secondary to a variety of AIDS complications including Pneumocystis pneumonia, CNS infections, or cancer.

b.  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.

7.  Temporal arteritis

8.  Idiopathic

E.  Reset osmostat

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

A.  Standard criteria

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

2.  Urine sodium is typically > 30 mEq/L in patients with a normal dietary intake of sodium. (Since patients are typically euvolemic, there is no stimulus to avidly reabsorb sodium and it is excreted.) However, patients with a low dietary intake of sodium (13–42% of patients) may have a low urine sodium and low FENa.

3.  Urine osmolality is inappropriately not maximally dilute. Urine osmolality > 100 mOsm/L and usually > 300 mOsm/L. (ADH leads to water reabsorption in the tubules, concentrating the urine.)

4.  Patients are not using diuretics.

5.  Patients are clinically euvolemic.

6.  Other causes of euvolemic hyponatremia must be excluded (hypothyroidism, psychogenic polydipsia, secondary adrenal insufficiency).

a.  Secondary adrenal insufficiency can cause euvolemic hyponatremia and mimic SIADH.

b.  Despite recommendations to rule out adrenal insufficiency in patients with suspected SIADH, only 33–41% of patients are appropriately evaluated for adrenal insufficiency.

c.  Secondary adrenal insufficiency is diagnosed in 3–4% of patients in whom SIADH is initially suspected. (In 59% of patients, the secondary adrenal insufficiency was due to exogenous steroid use.)

Treatment

A.  Determine and treat underlying etiology.

1.  Review medications. Discontinue any medications that may cause SIADH.

2.  Consider CT scan of the chest and head.

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

B.  It is important to note that isotonic saline without furosemide may worsen hyponatremia because ADH promotes water retention while the sodium is excreted.

Normal saline may worsen hyponatremia in patients with SIADH.

C.  Therapeutic options include fluid restriction < 800 mL/day, salt tablets, furosemide with salt tablets, hypertonic 3% saline, and ADH receptor antagonists.

1.  Fluid restriction < 800 mL/day is often used (except in patients with subarachnoid hemorrhage). Of note, fluid restriction is unlikely to be successful as the sole measure if urine osmolality is > 500 mOsm/L.

2.  Salt tablets can increase urine osmolality and facilitate increased water loss.

3.  Furosemide may be a useful adjunct to salt supplementation because it decreases the concentration of solute in the renal medulla (which creates the osmotic driving force for water retention), and thereby facilitates water excretion.

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

a.  Recommended for patients with severe neurologic symptoms (coma, seizures; Table 24-2)

b.  May also 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 24-2) in order to avoid subsequent ODS (Table 24-3).

(1)  Frequent sodium monitoring is critical to guide therapy. Although a large number of calculations have been used to predict the response to therapy (normal saline or 3% normal saline), the kidney’s response to therapy renders these frequently, and occasionally dangerously, inaccurate.

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

5.  ADH receptor antagonists (vaptans) can be used but caused rapid and dangerous increases in the serum sodium in 27% of patients with baseline sodium < 120 mEq/L. If used, patients require careful monitoring (see Tables 24-2, 24-3).

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

MAKING A DIAGNOSIS

As noted above, Mrs. L is clinically euvolemic with a serum osmolality of 265 mOsm/L, urine osmolality of 470 mOsm/L, and urine Na+ of 60 mEq/L.

Have you crossed a diagnostic threshold for the leading hypothesis, SIADH? Have you ruled out the other active alternatives that cause euvolemic hyponatremia? Do other tests need to be done to exclude the alternative diagnoses?

Mrs. L’s fulfills virtually all of the diagnostic criteria for SIADH. She is hypo-osmolar, clinically euvolemic, confirmed by her elevated urine sodium, with an elevated urine osmolality and has a normal TSH (ruling out severe hypothyroidism as an alternative cause). The only remaining criteria is to exclude adrenal insufficiency, which as noted previously, is potentially life-threatening disease that can mimic 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

A.  Pathophysiology

1.  Adrenal insufficiency may be primary or secondary.

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

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

2.  In both cases (primary and secondary adrenal insufficiency), cortisol levels are low. Cortisol normally suppresses ADH release. Decreased cortisol causes increased ADH levels and promotes hyponatremia.

3.  Primary adrenal insufficiency

a.  The destruction of the adrenal gland often results in decreased synthesis of other adrenal hormones as well as cortisol. Aldosterone, DHEA, and catecholamine synthesis may be impaired.

(1)  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.

(2)  DHEA deficiency affects women but not men (due to the presence of more potent testicular androgens). Findings may include decreased libido, decreased axillary and pubic hair, and amenorrhea.

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

b.  When secondary to autoimmune destruction (see below) may also be associated with other autoimmune diseases: hypothyroidism (47%), type 1 diabetes (12%), vitamin B12 deficiency (10%), and premature ovarian failure (6.6% of women)

4.  Secondary adrenal insufficiency (hypothalamic-pituitary insufficiency)

a.  Decreased ACTH results in decreased cortisol levels, increasing ADH and causing hyponatremia.

b.  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.

c.  May be associated with deficiencies of other pituitary hormones (ie, luteinizing hormone [LH], TSH) resulting in concomitant hypogonadism or hypothyroidism.

d.  Unlike primary adrenal insufficiency, the adrenal gland is not destroyed in secondary adrenal insufficiency. Since aldosterone secretion is primarily under control of the renin angiotensin system, it remains unaffected. Therefore, patients with secondary adrenal insufficiency are euvolemic and do not develop hyperkalemia.

B.  Etiology

1.  Etiologies of primary adrenal insufficiency

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

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

c.  Tuberculosis (most common cause in developing nations)

d.  Less common etiologies: Fungal or cytomegalovirus infections, bilateral adrenal hemorrhage (seen in septic shock, patients taking anticoagulants, meningococcemia, postoperative patients, and the anticardiolipin antibody syndrome), infiltration (cancer), inherited disorders and certain drugs (ketoconazole, rifampin, phenytoin, carbamazepine, St. John’s wort, and others)

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

a.  Iatrogenic due to corticosteroid therapy

(1)  Adrenal insufficiency may develop in up to 50% of patients taking long-term low-dose corticosteroid therapy (oral > 5 mg/day prednisone for > 3 months, inhaled, topical, or intra-articular).

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

b.  Sepsis

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

d.  Less common etiologies: Pituitary infarction, traumatic brain injury, irradiation, autoimmune hypophysitis, 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).

Evidence-Based Diagnosis

A.  History and physical exam

1.  Acute adrenal insufficiency (adrenal crisis):

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

b.  Occurs in 8% of patients with adrenal insufficiency per year; 6% of episodes fatal

c.  Often precipitated by inter-current stress (infection, emotional stress, surgery, pain, and many others)

d.  May be the initial manifestation of adrenal insufficiency

e.  Adrenal crisis may occur despite increase in glucocorticoids with stress.

f.  Occurs in patients with either primary or secondary adrenal insufficiency

2.  Chronic adrenal insufficiency

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

b.  Hypotension can be seen in both primary and secondary adrenal insufficiency due to the loss of vascular tone associated with hypocortisolism. It is more common in primary adrenal insufficiency (90%) due to concomitant aldosterone deficiency.

c.  Hyperpigmentation is seen only in primary adrenal insufficiency.

(1)  Underproduction of adrenal cortisol causes a compensatory increase in the release of proopiomelanocortin (POMC), the precursor hormone that contains both ACTH and melanocyte-stimulating hormone.

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

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

d.  Other findings in chronic adrenal insufficiency

(1)  Weakness, tiredness, fatigue: 100%

(2)  Weight loss and anorexia: 100%

(3)  Musculoskeletal complaints 94%

(4)  Gastrointestinal symptoms: nausea and vomiting 86–75%, 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.

(11)  Women may lose pubic and axillary hair in primary adrenal insufficiency due to the lack of adrenal androgens.

B.  Laboratory tests (Figure 24-5)

Figure 24-5. Diagnostic approach to suspected adrenal insufficiency.

1.  Guidelines suggest corticotropin stimulation testing (CST) in all cases of suspected adrenal insufficiency. However, in many patients, adrenal insufficiency can be ruled in or out with just a morning cortisol measurement, omitting the need for the more complex CST.

2.  Morning cortisol levels

a.  Cortisol secretion demonstrates a marked diurnal variation.

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

(1)  Morning levels ≥ 16.3 mcg/dL rule out adrenal insufficiency (99.2% sensitive).

(1)  Morning levels ≤ 3.6 mcg/dL establish adrenal insufficiency (98.4% specific).

(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.

(3)  Morning levels between 3.6 mcg/dL and 16.3 mcg/dL are nondiagnostic and necessitate CST.

3.  Corticotropin stimulation testing (CST)

a.  Useful in patients with indeterminate morning cortisol levels. (3.6–16.3 mcg/dL).

b.  Check 8 AM ACTH levels.

(1)  Elevated ACTH (suspected primary adrenal insufficiency)

(a)  Administer 250 mcg cosyntropin (synthetic ACTH) IM or IV.

(b)  Measure serum cortisol measured 60 minutes later.

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

(d)  92% sensitive

(2)  Low ACTH levels: suspected secondary adrenal insufficiency

(a)  Chronic (> 1 month) secondary or tertiary adrenal insufficiency results in adrenal atrophy. Adrenal atrophy results in nonresponse to the exogenous ACTH and a positive CST (level < 18 mcg/dL [500 nmol/L]).

(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 still stimulate the adrenal gland and cause 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.  This is a complex test that requires experience to avoid complications of hypoglycemia. Endocrine consultation is advised.

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

a.  Severe stressors often increase cortisol levels so that CST is often unnecessary.

b.  However, low cortisol levels must be interpreted with caution. Sick ICU patients often have low levels of cortisol binding globulin (CBG). Patients with low CBG may have low total cortisol levels but may in fact have normal levels of free cortisol and may not have adrenal insufficiency. Endocrine consultation is advised.

5.  Evaluation of confirmed primary adrenal insufficiency

a.  A search for the underlying etiology should include a careful review of medications, adrenal imaging with CT scanning, and quantiferon gold, HIV, and antibodies to 21-hydroxylase (to look for autoimmune adrenalitis).

b.  Patients with autoimmune adrenal insufficiency should be evaluated for other commonly associated autoimmune diseases (hypothyroidism, type 1 diabetes, vitamin B12 deficiency, and premature ovarian failure).

c.  Plasma aldosterone and plasma renin activity (PRA) should be measured to determine whether the patient is also mineralocorticoid deficient (elevated PRA with normal to low aldosterone is suggestive of deficiency).

6.  Evaluation of confirmed secondary adrenal insufficiency

a.  A pituitary MRI should be performed to look for tumors or infarction.

b.  Patients should be evaluated for the loss of other pituitary hormones.

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

a.  Hyponatremia develops in 88% of patients with primary or secondary adrenal insufficiency (secondary to hypocortisolism increasing ADH release).

b.  Hyperkalemia develops in 50% of patients with primary adrenal insufficiency due to aldosterone deficiency. It is not seen in patients with secondary adrenal insufficiency (because aldosterone secretion is normal).

c.  Hypercalcemia may be seen but is uncommon.

8.  Urine electrolytes in hyponatremic patients with adrenal insufficiency: Decreased cortisol secretion results in increased ADH levels and thereby results in laboratory values similar to SIADH (average urinary sodium, 110 mmol/L; average urine osmolality, 399 mOsm/L).

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

10.  Hypoglycemia is rare in adults.

Treatment

A.  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.  Glucocorticoid

a.  Daily dose: 15–25 mg hydrocortisone per day divided two or three times daily with highest dose in the morning.

b.  Prevention of adrenal crisis: Dosage should be increased for many stressors including strenuous physical activity, febrile illnesses, surgery, pregnancy, etc. In addition, patients should have available injectable hydrocortisone should they be unable to take oral medications and have a medic alert bracelet. Consultation is advised.

3.  Mineralocorticoid (in patients with primary adrenal insufficiency)

a.  Confirm deficiency by checking plasma renin activity and aldosterone levels.

b.  If aldosterone deficient, treat with 50–100 mcg/day of fludrocortisone

c.  Monitor potassium levels as well as BP

4.  DHEA (50 mg/day) can be considered for women with primary adrenal insufficiency and an impaired sense of well being or decreased libido despite glucocorticoid and mineralocorticoid replacement.

B.  Treatment of adrenal crisis

1.  Hydrocortisone 100 mg IV and then 50 mg IV every 6 hours for patients with confirmed or suspected adrenal crisis. Therapy should not be delayed for the results of diagnostic tests.

2.  Normal saline (often up to 1 L/h)

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

3.  Patients should be monitored closely to ensure that over-rapid correction of hyponatremia does not develop with steroid therapy (Table 24-2). 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.

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

CASE RESOLUTION

The patient’s morning cortisol was 1.2 mcg/dL. Her ACTH level was 6 mcg/mL (10–50 mcg/mL).

The patient’s very low cortisol level is diagnostic of adrenal insufficiency and her low ACTH makes the diagnosis of secondary adrenal insufficiency.

A follow-up MRI revealed a large pituitary adenoma (Figure 24-6). She was given replacement hydrocortisone and referred to endocrinology and neurosurgery for further evaluation.

Figure 24-6. MRI showing a large pituitary adenoma with signs of hemorrhage (arrow). (Reproduced with permission from Fountas A, Andrikoula M, Tsatsoulis A: A 45 year old patient with headache, fever, and hyponatraemia, BMJ. 2015 Feb 24;350:h962.)

Always rule out adrenal insufficiency prior to diagnosing patients with SIADH.

REVIEW OF OTHER IMPORTANT DISEASES

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

A.  One of the most common causes of hyponatremia

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

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

D.  More common in patients over 70 years (OR 3.9), and patients with a low body mass index

E.  56–70% of patients are women

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

G.  Usually develops within 2 weeks of initiation but may occur later if other risk factors for hyponatremia develop

H.  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.

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

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

Evidence-Based Diagnosis

A.  The diagnosis is based on history of thiazide use.

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

C.  Symptoms include lethargy 49%, dizziness 47%, vomiting 35%, confusion 17%, and seizures 0.9%.

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

Treatment

A.  Electrolytes should be check shortly after initiating thiazide diuretics.

B.  Symptomatic hyponatremia: See Table 24-2

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

D.  Hypovolemic patients

1.  Consider careful volume resuscitation with normal saline.

2.  Unlike euvolemic or hypervolemic patients, fluid resuscitation in a hypovolemic patient restores volume and thereby suppresses ADH. The fall in ADH may result in rapid water losses and an overly rapid and dangerous correction of the serum sodium concentration resulting in ODS (Table 24-3). 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 24-2).

Hypothyroidism

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

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

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

C.  Hyponatremia typically develops only 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 sufficient to trigger ADH release and are replaced with free water. Patients may have orthostatic hypotension or dry mucous membranes.

Disease Highlights

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

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

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

D.  Typical urine findings include

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

2.  Decreased FENa (< 0.5%)

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

4.  Prerenal azotemia (BUN/Cr > 20)

5.  Elevated uric acid

Evidence-Based Diagnosis

A.  The clinical exam has limited sensitivity for hypovolemia in hyponatremic patients.

B.  Spot urine sodium

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 FENa+.

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.  FENa+ may be more sensitive.

a.  FENa+ = (UNa+ × PCr)/(PNa+ × UCr)

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

c.  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:

a.  Diuretics

b.  Primary adrenal insufficiency in which the hypoaldosteronism impairs urinary sodium reabsorption and leads to sodium wasting.

c.  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.

a.  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.

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

Treatment

A.  For mildly symptomatic patients, normal saline can be used.

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

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

D.  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 24-2).

Hyponatremia with Normal or Hyper-osmolality & Pseudohyponatremia

Textbook Presentation

Patients with pseudohyponatremia typically present in 1 of 3 ways, depending on the underlying cause. Patients with pseudohyponatremia due to marked hyperlipidemia or hyperproteinemia, are usually asymptomatic and discovered incidentally due to laboratory testing. On the other hand, marked hyperglycemia may also cause hyponatremia and these patients usually present with symptoms of their severe hyperglycemia (polyuria, polydipsia, polyphagia, and dehydration) as well as the underlying precipitant. Patients with kidney failure often present with edema and may have neurologic signs caused by the uremia or hyponatremia or both.

Disease Highlights

A.  Because sodium is the major extracellular osmol, hyponatremia is almost always associated with hypo-osmolality.

B.  Occasionally, hyponatremia occurs in patients with either a normal or elevated serum osmolality. The conditions associated with hyponatremia and a normal or elevated serum osmolality include pseudohyponatremia, hyperglycemia, and uremia.

1.  Pseudohyponatremia

a.  Marked hyperlipidemia and marked hyperproteinemia may interfere with the accurate measurement of sodium and cause the sodium concentration to appear spuriously low and are therefore referred to as pseudohyponatremia.

b.  The actual serum sodium is normal.

c.  The measured serum osmolality is normal.

d.  These conditions should be suspected in patients with hyponatremia but normal serum osmolality.

2.  Marked hyperglycemia

a.  In poorly controlled diabetes, marked hyperglycemia acts as an osmotic agent and draws water into the extracellular space and thereby dilutes the sodium causing true hyponatremia. In this situation, the hyperglycemia makes the serum hyperosmolar.

b.  The elevated serum osmolality stimulates ADH release (decreasing free water clearance) which further accentuates the hyponatremia. (Hypernatremia may also occur if water intake is limited. See below.)

3.  Uremia:

a.  Kidney failure often interferes with free water clearance, causing water retention and true hyponatremia.

b.  However, the kidney failure also interferes with urea clearance and marked elevations in urea can occur increasing both the measured and calculated serum osmolality resulting in both true hyponatremia and an elevated or normal serum osmolality.

c.  Unlike hyperglycemia, urea crosses cell membranes and does not draw water into the intravascular space. Therefore, urea itself is not the cause of hyponatremia in kidney failure but is rather due to water retention.

Evidence-Based Diagnosis

A.  True hyponatremia always lowers the serum osmolality. Hyponatremic patients with a normal or elevated serum osmolality have pseudohyponatremia.

B.  The serum glucose, lipids, total protein, BUN, and creatinine should be measured.

C.  The serum sodium can be measured accurately by some point of care devices and blood gas analyzers.

D.  Marked hyperglycemia and an elevated serum osmolality suggests pseudohyponatremia due to hyperglycemia.

1.  Correction factors can help determine whether the hyponatremia is solely due to the hyperglycemia or some other cause. The optimal correction factor is controversial.

2.  Experiments suggest that hyperglycemia decreases the actual serum sodium concentration by 2.4 mEq/L for every 100 mg/dL elevation in blood glucose. This allows clinicians to estimate the serum sodium after the hyperglycemia is treated and the water relocates to the intracellular compartment.

3.  Corrected serum sodium = measured serum sodium + {2.4 *(glucose – 100)/100}

4.  For example, in a patient with a measured serum sodium of 122 mEq/L and glucose of 1000 mg/dL, the estimated corrected sodium followed treatment of the hyperglycemia = 122 + {2.4*(1000 – 100)/100) = 122 + 21.6 ≈ 144

Treatment

Treatment is directed at the underlying disorder.

MDMA (Ecstasy or Molly) 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

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

B.  Causes increased alertness, euphoria, sexual arousal, and disinhibition

C.  Frequent drug of abuse (up to 4.4–10% of high school seniors and 39% of US college students have reported use). Its use has been reported in 60–76% of rave participants. Accounted for 44% of patients requiring medical support at an electronic dance festival.

D.  Symptoms and signs among emergency department visits for MDMA use 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%).

E.  Serious complications have included hypoglycemia, hyponatremia, hyperthermia, malignant hypertension, stroke, CNS hemorrhage, coma, seizures, myocardial infarction, arrhythmias, aortic dissection, nontraumatic rhabdomyolysis, acute kidney injury, hepatitis, liver failure, disseminated intravascular coagulation, and death (even in first time users).

F.  Commonly ingested with other drugs

G.  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

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

B.  Numerous congeners of MDMA exist.

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

Treatment

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

B.  ICU monitoring is usually required.

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

D.  For marked symptoms (coma, seizures) hypertonic saline should be used (see Table 24-2). The risk of ODS is minimal in patients with MDMA-induced hyponatremia because the hyponatremia is acute.

HYPERNATREMIA

CHIEF COMPLAINT

PATIENT

Mr. R is an 80-year-old nursing home resident with a history of severe dementia. He has been brought to the emergency department with lethargy and confusion. Serum chemistries reveal a sodium level of 168 mEq/L.

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; hypernatremia is found on serum chemistries. 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 (defined as serum sodium > 145 mEq/L) 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 not only of ADH, but also 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. The magnitude of the hypernatremia 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. (See Chapter 12, Diabetes.)

Other causes of hypernatremia are rare and will be touched upon here only briefly. Hypernatremia may develop in patients with impaired 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 serum 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.

Figure 24-7. Approach to hypernatremia.

Differential Diagnosis of Hypernatremia

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

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

2.  Water unavailable (ie, desert conditions)

B.  Osmotic diuresis with impaired water intake

1.  Hyperosmolar hyperglycemia

2.  Postobstructive diuresis

C.  Rare etiologies

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

a.  Neurogenic diabetes insipidus (decreased ADH production)

b.  Nephrogenic diabetes insipidus (ADH resistance)

(1)  Long-term lithium ingestion

(2)  Hypercalcemia

2.  Hypothalamic lesions causing decreased thirst

3.  Increased salt intake

a.  Salt water ingestion

b.  Hypertonic saline

c.  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.

Table 24-8. Findings in patients with hypernatremia.

RANKING THE DIFFERENTIAL DIAGNOSIS

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.

Table 24-9. Diagnostic hypotheses for Mr. R.

The nursing home reports that Mr. R has had a cough for the last 3 days with low-grade fever. Over the last 48 hours, he has become progressively less responsive and his oral intake and urinary output have dropped dramatically.

Mr. R is minimally responsive to stimuli. Vital signs are BP, 110/70 mm Hg; pulse, 110 bpm; temperature, 38.1°C; RR, 20 breaths per minute. His oral mucosa is parched and his axilla dry. Lung exam is difficult to evaluate due to poor effort. Cardiac exam reveals tachycardia; neck veins are flat. There is no S3 or S4. Laboratory findings: Na, 168 mEq/L; K, 4.2 mEq/L; HCO3−, 24 mEq/L; chloride, 134 mEq/L; BUN, 45 mg/dL; creatinine, 1 mg/dL. Serum glucose is 150 mg/dL.

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

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

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

B.  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, although this occurs almost exclusively in children.

C.  Hypernatremia should be corrected slowly ≅ 0.4 mEq/L/h (≤ 10 mEq/L/day).

D.  A recommended approach includes the following:

1.  Normal saline to correct the patient’s concomitant volume deficit

a.  Hypernatremic patients are usually markedly hypovolemic. If hypotensive, they may be 10% dehydrated (7L in a 70-kg man).

b.  Often patients will take several 1-liter boluses to improve BP, resolve orthostasis, and improve urinary output.

c.  Normal saline boluses commonly administered as 500–1000 mL over 1 hour

d.  Patients should be reevaluated after each bolus. Vital signs and orthostasis should be rechecked, and patients should have a careful heart and lung exam to ensure they are not receiving excessive fluid. Urinary output should be monitored.

e.  Once BP and urinary output are restored, boluses can be stopped and the remaining fluid deficit divided over the next 48 hours.

2.  D5W @ 1.35 mL/hour/kg should be administered to restore the free water deficit and correct hyponatremia by < 10 mEq/L/day.

3.  Add ongoing free water losses, if any.

4.  Remeasure serum sodium frequently (every 4–6 hours) to ensure rate is neither too excessive nor too slow.

MAKING A DIAGNOSIS

Mr. R’s urine osmolality is 850 mOsm/L.

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

A chest film reveals a right lower lobe pneumonia. Blood cultures grow Streptococcus pneumoniae.

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. The cause of his deterioration is evident (his pneumonia and bacteremia). Further diagnostic testing is not required.

CASE RESOLUTION

Mr. R is given D5W. His body weight is measured at 140 lbs (63 kg). The rate of free water administration must be determined. He is given piperacillin-tazobactam to treat his aspiration pneumonia.

Three days after D5W is started, his electrolytes are normal. He gradually returns to his baseline neurologic function and is discharged after 6 days of therapy to continue his oral antibiotics at the nursing home.

Hyperosmolar Hyperglycemic State

See Chapter 12, Diabetes.

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