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Because Na is the major osmotically active ion in the ECF, total body Na content determines ECF volume. Deficiency or excess of total body Na content causes ECF volume depletion or overload. Serum Na concentration does not necessarily reflect total body Na.
Dietary intake and renal excretion regulate total body Na content. When total Na content and ECF volume are low, the kidneys increase Na conservation. When total Na content and ECF volume are high, Na excretion (natriuresis) increases so that volume decreases.
Renal Na excretion can be adjusted widely to match Na intake. Renal Na excretion requires delivery of Na to the kidneys and so depends on renal blood flow and GFR. Thus, inadequate Na excretion may be secondary to decreased renal blood flow, as in chronic kidney disease or heart failure.
Renin-angiotensin-aldosterone axis
The renin-angiotensin-aldosterone axis is the main regulatory mechanism of renal Na excretion. In volume-depleted states, GFR and Na delivery to the distal nephrons decreases, causing release of renin. Renin cleaves angiotensinogen (renin substrate) to form angiotensin I. ACE then cleaves angiotensin I to angiotensin II. Angiotensin II does the following:
Angiotensin I can also be transformed to angiotensin III, which stimulates aldosterone release as much as angiotensin II but has much less pressor activity. Aldosterone release is also stimulated by hyperkalemia.
Other natriuretic factors
Several other natriuretic factors have been identified, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and a C-type natriuretic peptide (CNP).
ANP is secreted by cardiac atrial tissue. Concentration increases in response to ECF volume overload (eg, heart failure, chronic kidney disease, cirrhosis with ascites) and primary aldosteronism and in some patients with primary hypertension. Decreases have occurred in the subset of patients with nephrotic syndrome who have presumed ECF volume contraction. High concentrations increase Na excretion and increase GFR even when BP is low.
BNP is synthesized mainly in the atria and left ventricle and has similar triggers and effects to ANP. BNP assays are readily available. High BNP concentration is used to diagnose volume overload.
CNP, in contrast to ANP and BNP, is primarily vasodilatory.
Na depletion and excess
Na depletion requires inadequate Na intake plus abnormal losses from the skin, GI tract, or kidneys (defective renal Na conservation). Defective renal Na conservation may be caused by primary renal disease, adrenal insufficiency, or diuretic therapy.
Na overload requires higher Na intake than excretion; however, because normal kidneys can excrete large amounts of Na, Na overload generally reflects defective regulation of renal blood flow and Na excretion (eg, as occurs in heart failure, cirrhosis, or chronic kidney disease).
Volume Depletion
Volume depletion, or ECF volume contraction, occurs as a result of loss of total body Na. Causes include vomiting, excessive sweating, diarrhea, burns, diuretic use, and kidney failure. Clinical features include diminished skin turgor, dry mucous membranes, tachycardia, and orthostatic hypotension. Diagnosis is clinical. Treatment involves administration of Na and water.
Because water crosses plasma membranes in the body through passive osmosis, loss of the major extracellular cation (Na) quickly results in water loss from the ECF space as well. In this way, Na loss always causes water loss. However, depending on many factors, serum Na concentration can be high, low, or normal in volume-depleted patients (despite the decreased total body Na content). ECF volume is related to effective circulating volume. A decrease in ECF (hypovolemia) generally causes a decrease in effective circulating volume, which in turn causes decreased organ perfusion and leads to clinical sequelae. Common causes of volume depletion are listed in Table 1: Fluid Metabolism: Common Causes of Volume Depletion .
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Table 1
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| Common Causes of Volume Depletion |
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Type
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Examples
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Extrarenal
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Bleeding
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GI bleeding
Trauma
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Dialysis
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Hemodialysis
Peritoneal dialysis
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GI
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Diarrhea
Nasogastric suction
Vomiting
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Skin
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Burns
Excessive sweating
Exfoliation
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3rd-space losses
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Intestinal lumen
Intraperitoneal
Retroperitoneal
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Renal, adrenal, and pituitary
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Acute renal failure
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Diuretic phase of recovery
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Adrenal disorders
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Adrenal insufficiency (causing adrenal steroid deficiency), including Addison disease
Hypoaldosteronism
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Genetic disorders causing hyperaldosteronism and renal Na and K wasting
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Bartter syndrome
Gitelman syndrome
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Hypothalamic or pituitary disorders causing ADH deficiency
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Diabetes insipidus (central, eg due to trauma, tumor, infection)
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Osmotic diuresis
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Diabetes mellitus with extreme glucosuria
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Diuretics
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Loop diuretics
Thiazide diuretics
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Salt-wasting renal disease
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Interstitial nephritis
Medullary cystic disease
Myeloma (occasionally)
Pyelonephritis (occasionally)
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Symptoms and Signs
In mild volume depletion (< 5% of ECF), the only sign may be diminished skin turgor (best assessed at the upper torso). Skin turgor may be low in elderly patients regardless of volume status. Patients may complain of thirst. Dry mucous membranes do not always correlate with volume depletion, especially in the elderly and in mouth-breathers. Oliguria is typical.
When ECF volume has diminished by 5 to 10%, orthostatic tachycardia, hypotension, or both are usually, but not always, present. Also, orthostatic changes can occur in patients without ECF volume depletion, particularly patients deconditioned or bedridden. Skin turgor may decrease further.
When fluid loss exceeds 10% of ECF volume, signs of shock (eg, tachypnea, tachycardia, hypotension, confusion, poor capillary refill) can occur.
Diagnosis
Volume depletion is suspected in patients at risk, most often in patients with a history of inadequate fluid intake (especially in comatose or disoriented patients), increased fluid losses, diuretic therapy, and renal or adrenal disorders.
Diagnosis is usually clinical. When the cause is obvious and easily correctable (eg, acute gastroenteritis in otherwise healthy patients), laboratory testing is unnecessary; otherwise, serum electrolytes, BUN, and creatinine are measured. Plasma osmolality and urine Na, creatinine, and osmolality are measured when there is suspicion of clinically meaningful electrolyte abnormality that is not clear from serum tests and for patients with cardiac or renal disease. When metabolic alkalosis is present, urine Cl is also measured.
Central venous pressure and pulmonary artery occlusion pressure are decreased in volume depletion, but measurement is rarely required. Measurement, which requires an invasive procedure, is occasionally necessary for patients for whom even small amounts of added volume may be detrimental, such as those with unstable heart failure or advanced chronic kidney disease.
The following concepts are helpful when interpreting urine electrolyte and osmolality values:
Volume depletion frequently increases the BUN and serum creatinine concentrations with the ratio of BUN to creatinine often > 20:1. Values such as Hct often increase in volume depletion but are difficult to interpret unless baseline values are known.
Treatment
The cause of volume depletion is corrected and fluids are given to replace existing volume deficits as well as any ongoing fluid losses and to provide daily fluid requirements. Mild-to-moderate volume deficits may be replaced by increased oral intake of Na and water when patients are conscious and not vomiting. When volume deficits are severe or when oral fluid replacement is impractical, IV 0.9% saline is given. Typical IV regimens are discussed in Shock and Fluid Resuscitation: Intravenous Fluid Resuscitation; oral regimens are discussed in Dehydration and Fluid Therapy in Children: Oral Rehydration.
Volume Overload
Volume overload generally refers to expansion of the ECF volume. ECF volume expansion typically occurs in heart failure, nephrotic syndrome, and cirrhosis. Renal Na retention leads to increased total body Na content. This increase results in varying degrees of volume overload. In heart failure, the increased ECF volume results in decreased effective circulating volume, which in turn causes decreased organ perfusion leading to clinical sequelae. Serum Na concentration can be high, low, or normal in volume-overloaded patients (despite the increased total body Na content).
An increase in total body Na is the key pathophysiologic event. It increases osmolality, which triggers compensatory mechanisms that cause water retention. When sufficient fluid accumulates in the ECF (usually > 2.5 L), edema (see Symptoms of Cardiovascular Disorders: Edema) develops.
Among the most common causes of ECF volume overload are the following:
Clinical features include weight gain and edema. Diagnosis is clinical.
Treatment aims to correct the cause. Dietary sodium intake is restricted (except in SIADH). Diuretics are given in heart failure, cirrhosis, kidney failure, and nephrotic syndrome. The location and amount of edema is dependent on many factors, including whether the patient has been sitting, lying, or standing recently. Daily weights are the best way to follow the progress of therapy for ECF volume overload. The speed of correction of ECF volume overload should be limited to 0.25 to 0.5 kg body weight/day, depending on the degree of volume overload (faster with a copious excess, slower with less excess) and the patient's other medical problems (slower with hypotension and kidney disease).
Last full review/revision October 2012 by James L. Lewis, III, MD
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