Why Are Disorders of Sodium Concentration So Difficult?

There are two important reasons why sodium concentration disorders (dysnatremias) are challenging. First, making the correct clinical diagnosis can be difficult. Second, the correct treatment regimen in acutely symptomatic patients is a high-stakes issue, as incorrect treatment can lead to a catastrophic outcome. With acute symptomatic hyponatremia, failure to rapidly raise the plasma sodium in a patient with cerebral edema may result in permanent brain damage or even herniation and death, whereas raising the plasma sodium too much may cause permanent brain damage due to the development of osmotic demyelination syndrome (ODS). In the 1980s, there was a controversy in the literature and a series of debates at nephrology meetings, with Allen Arieff on the side of rapid correction (Arieff, 1986) and Richard Sterns preaching caution (Sterns et al., 1986). Robert Narins wondered if it was really true that “haste made waste” (Narins, 1986). Actually, both sides can be correct, depending on the situation. In the rare patient with acute symptomatic hyponatremia (occurring within minutes to hours), rapid correction is necessary to treat brain edema. In most patients, however, even symptomatic hyponatremia is chronic (>48 hours in duration), and caution is advised. A 1989 article by Sterns “The Treatment of Hyponatremia: Unsafe at Any Speed?” followed by his 1990 article “The Treatment of Hyponatremia: First, Do No Harm,” and a 1990 discussion by Tomas Berl “Treating Hyponatremia: Damned If We Do and Damned If We Don’t” pointed out that the brain is encased in a skull and thus there is a limit to the amount of brain edema that can occur without leading to herniation and death (Sterns, 1989, 1990; Berl, 1990). Brain water content therefore cannot exceed about 10% above normal. Thus, it follows that if symptoms
are due to cerebral edema, they should be corrected by an increase in serum sodium of 10% or less regardless of the severity of hyponatremia.

It is of interest that we seem to have come full circle in our views on management of acute symptomatic hyponatremia. In the first edition of Harrison’s Principles of Internal Medicine, published in 1950, it was recommended that patients with symptomatic water intoxication promptly receive hypertonic saline to increase the plasma sodium by about 2 to 6 mmol/L. Currently, marathon runners with acute symptomatic hyponatremia due to water intoxication are treated in a similar fashion (Hew-Butler et al., 2008); most authorities today favor rapid correction of up to 6 mmol/L in severely symptomatic patients and to avoid an increase in plasma sodium of more than 8 mmol/L in the first 24 hours (Sterns, 2014). Such a regimen should provide the benefit of treating cerebral edema while minimizing the chance of the later development of ODS.

PATHOGENESIS OF HYPONATREMIA

We will now address the pathogenesis of hyponatremia. On occasion, the plasma sodium concentration [Na] may be artifactually low, that is, pseudohyponatremia. In such cases, the plasma osmolality is normal rather than low as would be expected. This used to be rather commonly observed in the presence of hyperglobulinemia (such as myeloma) or marked hypertriglyceridemia. Fortunately, this now rarely occurs with modern laboratory methods, except at extremes of globulin or triglyceride concentrations, and further discussion will be focused on true hyponatremia. Patients with high plasma concentrations of an osmotically active substance (usually glucose, but sometimes mannitol or other substances) can develop hyperosmolal hyponatremia due to shift of water from the intracellular (ICF) to extracellular fluid (ECF). Most patients with hyponatremia, however, have hypoosmolal hyponatremia.

In true hyponatremic states, the plasma [Na] reflects the relative amount of sodium to water in the plasma, but does not give any information about the absolute amount of either, which must be determined clinically. Thus, the clinician must determine the meaning of the plasma [Na] in the context of the patient’s clinical picture, and in particular the volume status. Therefore, we classify hypoosmolal hyponatremic patients as being hypovolemic, euvolemic, or hypervolemic, depending on the clinically perceived assessment of ECF volume (Table 7.1). If a patient has no edema, flat neck veins, and an orthostatic fall in blood pressure (with an increase in heart rate), this is a fairly reliable indication of volume depletion. If there is edema, this is good evidence for ECF excess or
hypervolemia. If neither is present, we say that the patient is euvolemic. However, it is not always easy to determine ECF volume status at the bedside. In some situations (e.g., severe hypoalbuminemia, inferior vena cava compression), edema may be due to alteration in Starling forces (i.e., the ECF, which is usually distributed in an approximately 1:3 ratio between plasma and interstitial fluid, is now preferentially distributed in the interstitial space compared to the plasma). Such patients may actually be plasma-volume depleted despite having edema. This is not at all uncommon in the ICU setting. Moreover, despite edema, many patients have a decrease in what has been termed “effective blood volume,” meaning that even though the ECF is expanded, there is activation of neurohormonal pathways that signal the kidneys that effective volume is low and to conserve salt and water. Common examples are congestive heart failure (where low cardiac output is perceived as low effective volume) and liver cirrhosis (where systemic vasodilatation is perceived as low effective volume) despite the presence of ascites and/or edema. In all of these
conditions, hyponatremia will be present if there is a relatively greater increase in total body water (TBW) relative to total body sodium (TBNa).

TABLE 7.1 Causes of Hypoosmolar Hyponatremia

Hypovolemic		Euvolemic	Hypervolemic
FENa <1; Uosm > Posm	FENa >1; Uosm ˜ or > Posm	FENa usually >1; Uosm > Posm except < Posm in reset osmostat, psychogenic polydipsia, and beer drinker’s syndrome	FENa <1; Uosm > Posm	FENa >1; Uosm ˜ Posm
GI or sweat losses	Salt-losing nephropathy	SIADH/Reset osmostat/NSIAD	CHF	Renal failure
	Adrenal insufficiency/isolated	Psychogenic polydipsia	Cirrhosis
	Mineralocorticoid deficiency	Beer drinker’s syndrome	Nephrotic syndrome
	Diuretics	Exercise hyponatremia
		Postoperative hyponatremia
		Drugs either stimulating ADH secretion or increasing its action
FENa, fractional excretion of sodium; Uosm, urine osmolality; Posm, plasma osmolality; GI, gastrointestinal;
NSIAD, nephrogenic syndrome of inappropriate antidiuresis; ADH, antidiuretic hormone; CHF, congestive heart failure.
From Moinuddin IK, Leehey DJ. Handbook of Nephrology. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.

To add additional difficulty, we also need to be concerned about potassium in addition to sodium and water when we are analyzing sodium problems. Why? The answer lies in the fact that whereas sodium is essentially confined to the ECF, potassium is mostly in the ICF. Administration of sodium will increase the content of sodium in the ECF; the increase in ECF [Na] will then draw water out of the ICF by osmosis. The change in plasma [Na] will thus depend on the amount of sodium administered and the sum of ECF and ICF volume, that is, TBW. On the other hand, administration of potassium will increase the content of potassium in the ICF; the increase in ICF [K] will draw water into the cells, thus increasing the plasma [Na].

Since ECF [Na] is approximately equal to ICF [K]:

Plasma [Na] = (TBNa + TBK)/TBW Plasma [Na] thus reflects the relationship between total body cations (sodium plus potassium) and TBW. This concept was first proposed and provided experimental evidence by Edelman and colleagues in 1958. Edelman’s formula was a bit more complex since not all sodium in the body is osmotically active, but the simpler formula works well in clinical practice.

Administration of water will lead to a decrease in plasma [Na]. In a healthy individual, a very small (˜1%) decrease in plasma sodium or osmolality will inhibit antidiuretic hormone secretion with resultant water diuresis, serving to normalize the plasma [Na]. Thus, with rare exceptions, hypoosmolal hyponatremia is due to impaired renal water excretion.

Assuming there has not been time for renal water excretion to occur or there is a pronounced defect in renal water excretion, how does one calculate the predicted change in plasma [Na+] with addition of water to the body?

Using a formula derived from Avogadro’s law:

V₁ × C₁ = V₂ × C₂

where V₁ = initial TBW; V₂ = final TBW; C₁ = initial plasma [Na]; and C₂ = final plasma [Na].

The TBW is generally estimated as 0.6 × body weight (kg) in men (0.5 × body weight in women). In a 70-kg male patient, the TBW would thus be 42 L. If the initial plasma [Na] is 140 mmol/L, and 3 L of water is added to the body (with no water losses), the TBW is now 45 L.

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