Evaluation of the Extracellular Fluid Volume
Disorders of extracellular fluid volume are disorders of sodium balance and total body sodium content. The terms volume contraction and volume expansion are frequently employed as shorthand to indicate extracellular fluid (ECF) volume contraction and expansion, respectively. Because ECF volume control systems are largely distinct from systems that regulate plasma osmolality, disorders of ECF volume are commonly distinguished from disorders of water balance. The term dehydration is commonly used to indicate ECF volume depletion; strictly, its use should be reserved for depletion of water (as in diabetes insipidus) rather than ECF volume.
Disorders of ECF volume have long presented a challenge in the understanding of body fluid volume regulation. In the normal subject, if ECF is expanded, the kidney will excrete the excessive amount of sodium and water, thus returning ECF volume to normal. What has not been understood, however, is why the kidneys continue to retain sodium and water in edematous patients. Neither total ECF nor its interstitial component, both of which are expanded in the patient with generalized edema, is the modulator of renal sodium and water excretion. Rather, some body fluid compartment other than total ECF or interstitial fluid volume must be the regulator of renal sodium and water excretion.
The term effective blood volume was coined to describe this undefined body fluid compartment that signals the kidney, through unknown pathways, to retain sodium and water in spite of expansion of the total ECF volume. It was first suggested that the kidney is responding to a decline in cardiac output, providing an explanation for sodium and water retention in low-output cardiac failure. This idea, however, did not provide a universal explanation for generalized edema, because many patients with decompensated cirrhosis who avidly retain sodium and water have normal or elevated cardiac output. The venous component of the plasma in the circulation was also proposed as the modulator of renal sodium and water excretion because a rise in the left atrial pressure is known to cause a water diuresis and natriuresis, mediated in part by a suppression of vasopressin and an increase in secretion of atrial and B-type natriuretic peptides. These factors also cannot fully explain ECF volume homeostasis, because renal sodium and water retention are hallmarks of congestive heart failure—a situation in which pressures in the atria and venous component of the circulation are increased.
The arterial portion of body fluids is the remaining component that may be pivotal in the regulation of renal sodium and water excretion. The relation between cardiac output and peripheral arterial resistance [termed the effective arterial blood volume (EABV)] has been proposed as a regulator of renal sodium and water reabsorption. In this context, either a decrease in cardiac output or vasodilation of the arterial tree may cause arterial underfilling and thereby initiate and sustain a sodium and water-retaining state.
Two major compensatory processes respond to arterial underfilling. One is very rapid, consisting of a neurohumoral and systemic hemodynamic response. The other is slower and involves renal sodium and water retention. In the edematous patient, these compensatory responses have usually occurred to varying degrees when the patient is seen. Whether a primary fall in cardiac output or peripheral arterial vasodilation is the initiator of arterial underfilling, the compensatory responses are quite similar and involve the stimulation of the sympathetic nervous system, the renin/angiotensin system, and vasopressin. With a decrease in ECF volume, as occurs with acute gastrointestinal losses, sufficient sodium and water retention can occur to restore cardiac output to normal and terminate renal sodium and water retention before edema forms. Such may not be the case with low-output cardiac failure because even these compensatory responses may not restore cardiac output to normal. Because of the compensatory processes described above, mean arterial pressure is an insensitive indicator of arterial fullness.
Hypovolemia
- History of blood loss, gastrointestinal losses, or excessive sweating.
- History of diuretic use.
- Tachycardia and postural hypotension.
- The jugular venous pulse is not visible.
Hypovolemia reflects a decrease in ECF volume (normal body fluid volumes are given in Table 2–1). The ECF volume declines when losses (NaCl losses or losses of ECF) exceed input. Simply reducing dietary NaCl intake leads to a modest decline in ECF volume, with a reduction in total body Na content approximating the reduction in daily Na intake in millimoles. Typical western diets include 4–6 g of Na (43 mmol/g of Na). Although reduced NaCl intake can lead to mild ECF volume depletion, the effects are usually not clinically significant because normal kidneys can reduce urinary NaCl excretion to very low levels.
Compartment volume in 70-kg person | Amount | Volume (L) |
|---|---|---|
Total body fluid | 60% of body weight | 42 |
Intracellular fluid (ICF) | 40% of body weight | 28 |
Extracellular fluid (ECF) | 20% of body weight | 14 |
Interstitial fluid | Two-thirds of ECF | 9.4 |
Plasma fluid | One-third of ECF | 4.6 |
Venous fluid | 85% of plasma fluid | 3.9 |
Arterial fluid | 15% of plasma fluid | 0.7 |
ECF losses frequently occur via one of four routes: gastrointestinal, renal, integumentary, or into a “third space.” A history of vomiting or diarrhea frequently precipitates ECF volume depletion, especially because gastrointestinal disorders are frequently associated with reduced intake. Excessive renal losses typically occur secondary to intrinsic salt-wasting disorders of the kidney, to the administration of salt-wasting diuretic drugs, or to osmotic losses via the urine, such as occur during poorly controlled diabetes.
A history of previous renal disease, familial salt wasting, or diuretic use points to salt wasting (see Table 2–2). Symptoms of polyuria, polydipsia, and polyphagia suggest diabetes. Generic symptoms of ECF volume depletion include thirst and salt craving. Patients with Addison’s disease frequently manifest symptoms of lassitude. Individuals with inherited salt wasting frequently describe the desire to drink pickle juice or ingest large amounts of salty foods. When ECF volume depletion is more severe, the symptoms result from reduced plasma volume; these include weakness and eventually loss of consciousness.
| I. Renal |
| A. Chronic kidney disease |
| B. Postacute renal failure |
| C. Postobstructive |
| D. Renal tubular acidosis |
| II. Extrarenal |
| A. Mineralocorticoid deficiency |
| 1. Addison’s disease |
| 2. Isolated hypoaldosteronism |
| B. Natriuretic peptide-mediated |
| 1. Cerebral salt wasting |
| 2. SIADH |
| III. Drug-induced |
| A. Solute diuresis |
| 1. Mannitol |
| 2. Urea |
| 3. Glucose |
| 4. Bicarbonate |
| B. Diuretics |
| 1. Proximal |
| 2. Loop |
| 3. DCT |
| 4. CCT |
If the skin on the thigh, calf, or forearm is pinched in normal subjects, it will immediately return to its normally flat state when the pinch is released. The speed at which the skin returns to its normal flat state after being pinched is often called “skin turgor.” A diminished turgor has frequently been suggested to indicate depletion of the ECF volume, but a systematic review found this sign to have no diagnostic value in adult patients. In contrast, dry axillae may suggest ECF volume depletion, whereas moist axillae argue against it. Dryness of the mucous membranes of the mouth and nose and longitudinal furrows on the tongue have also been shown to indicate ECF volume depletion.
Changes in pulse rate and arterial pressure may indicate ECF volume depletion. When the ECF volume depletion is mild, only postural changes may be evident. Clinicians measuring postural changes should wait at least 2 minutes before measuring the supine vital signs and 1 minute after standing before measuring the upright vital signs. Counting the pulse for 30 seconds and doubling the result is more accurate than 15 seconds of observation. In normovolemic individuals, a postural pulse increment of more than 30 beats/minute is uncommon, affecting only about 2–4% of individuals.
The most helpful physical findings in the setting of blood loss are severe postural dizziness (preventing measurement of upright vital signs) or a postural pulse increment of 30 beats/minute or more. Postural changes on sitting are much less reliable. After excluding those unable to stand, postural hypotension has no incremental diagnostic value.
The reduction in the vascular volume observed with hypovolemia occurs primarily in the venous circulation (which normally contains 70% of the blood volume), thereby leading to a decrease in venous pressure. As a result, estimation of the jugular venous pressure is useful to confirm the diagnosis of hypovolemia and to assess the adequacy of volume replacement. Details concerning examination of the jugular venous pressure are presented below (ECF volume expansion). It is important to remember that a low jugular pressure (wherein the jugular pulse cannot be observed) may be normal and is consistent with, but never diagnostic of, hypovolemia.
Most information concerning the state of ECF volume is obtained from the history and physical examination. Laboratory tests provide additional information, in some situations. It is worth reemphasizing that abnormalities of serum sodium concentration do not indicate the ECF volume. A hyponatremic patient may be hypovolemic, euvolemic, or hypervolemic, depending on clinical circumstances. Nevertheless, abnormal values for serum Na concentration suggest consideration of volume disorders. Further, abnormalities of serum K, Cl, or HCO3 also suggest disorders of ECF volume. Hypokalemic metabolic alkalosis is most commonly associated with ECF depletion. Yet hypokalemic alkalosis may also be associated with hypervolemia; thus constellations of electrolyte abnormalities are not generally used to diagnose disorders of ECF volume.
Some laboratory findings do provide useful indications of ECF volume depletion. The ratio of blood urea nitrogen to creatinine, when expressed in mg/dL, frequently exceeds 20:1, when azotemia results from depletion of the ECF volume. Hemoconcentration and increases in serum uric acid concentration may also be observed. In the setting of acute renal failure, a fractional sodium excretion less than 1% suggests prerenal azotemia, which may be the result of ECF volume depletion. Yet prerenal azotemia also occurs in the setting of congestive heart failure, where the ECF volume is expanded. Thus, urine chemistry may help to determine the state of the “effective” arterial volume, but is less useful for determining ECF volume itself. As described above, hypokalemic metabolic alkalosis may be associated with an ECF volume depleted or expanded state. A urine Cl concentration of less than 10–15 mM is taken as evidence that the alkalosis is related to ECF volume depletion and should be chloride responsive.
Depletion or expansion of the ECF volume may be estimated by ultrasound or echocardiography. This approach is often restricted to patients in the intensive care unit but appears to be reliable. The diameter of the inferior vena or its collapse during inspiration indicates ECF volume depletion.
A measured central venous pressure provides definitive evidence of the filling pressure of the venous circulation. Placement of a pulmonary artery catheter can provide information about the left-sided filling pressure, but this technique has become less commonly employed because controlled studies suggest that it does not improve outcome.
Many times, the differential diagnosis of ECF volume depletion is clear. On some occasions, however, the etiology is less obvious. Individuals may ingest diuretics surreptitiously, leading to hypokalemic alkalosis with volume depletion. In this situation, the urine Na and Cl concentration may be increased despite ECF volume depletion, making the diagnosis difficult. In contrast, bulimia will cause ECF volume depletion and metabolic alkalosis, in association with a very low urinary Cl concentration.
Several rare inherited or acquired diseases of kidney ion transport present with renal salt wasting. Depending on their severity and the clinical setting, salt-wasting disorders may present as unrelenting polyuria with extreme depletion of the ECF volume leading rapidly to death or as mild but troubling syndromes in which depletion of the ECF volume is nearly undetectable. Several clinical features, however, are typical of most salt-wasting disorders. These features include malaise, lassitude, fatigability, and salt craving. When mild, these symptoms can be subtle enough to lead to diagnostic difficulty. A classification of salt-wasting disorders is shown in Table 2–2.
Progressive and severe hypovolemia causes organ dysfunction, including prerenal azotemia. The kidney is especially sensitive to depletion of the ECF volume or the EABV and responds by increasing retention of NaCl and water. These effects tend to restore ECF volume, but prerenal azotemia can also lead to uremia and acute tubular necrosis, if the ECF volume depletion remains untreated.
When even more severe, hypovolemia can lead to a state of shock in which the perfusion of vital organs is inadequate to meet physiological needs. In this setting, frank hypotension is present, the patient is cool and often dusky, and the mentation is impaired.
The essential factors in treating hypovolemic conditions are to remove ongoing precipitants and correct the ECF volume depletion. Clearly, the physician should address ongoing blood, gastrointestinal, or sweat losses appropriately. When excessive diuretic use has contributed to ECF volume depletion, diuretics should be discontinued.
The choice of repletion method depends on the severity of symptoms, the nature of the losses, and the presence of superimposed disorders of osmolality (see Table 2–3). Mild ECF volume depletion frequently responds to provision of dietary NaCl and water. One of the most common causes of ECF volume depletion worldwide is infectious diarrhea, especially in children. Oral rehydration solutions (ORS) have become the standard by which all but the most serious cases are treated (see Table 2–4). These have had a dramatic impact on mortality.
No Signs of Dehydration | Some Dehydration | Severe Dehydration | |
|---|---|---|---|
Mental state | Well, alert | Restless, irritable | Lethargic |
Appearance of eyes | Normal | Sunken | Sunken |
Thirst | Not thirsty | Thirsty, drinks eagerly | Drinks poorly |
Skin pinch | Normal | Returns slowly | Returns very slowly |
Estimated degree of dehydration | <5% or <50 mL/kg | 5–10% or 50–100 mL/kg | >10% or >100 mL/kg |
Suggested treatment | Treat at home
| Rehydration at health center; give ORS-based on weight; assess response; give zinc, food on discharge | Intravenous rehydration in hospital where possible; if not available, nasogastric ORS is suggested |
Recommended rehydration therapy | Not recommended | ||||
|---|---|---|---|---|---|
“Standard” ORS (WHO, 1975) | Reduced-osmolarity ORS (WHO, 2002) | Rice-based ORS (eg, Ceralyte) | Gatorade | Coke | |
Glucose (g/L) | 111 | 75 | — | — | — |
Carbohydrate (g/L) | — | — | 40 | 60 | 110 |
Sodium (mEq/L) | 90 | 75 | 50–90 | 20 | 6 |
Potassium (mEq/L) | 20 | 20 | 20 | 3 | |
Chloride (mEq/L) | 80 | 65 | 40 | 14 | 26 |
Citrate (mEq/L) | 10 | 10 | 30 | 3 | |
Osmolarity (mOsm/L) | 311 | 245 | 225–275 | 350 | 650 |
When the ECF volume depletion is more severe, resuscitation with intravenous fluids is indicated. Intravenous saline or Ringer’s lactate have been shown to restore ECF volume and hemodynamic stability effectively. Using albumin or starch-containing solutions does not appear to improve effectiveness. Ringer’s lactate has the advantage of avoiding hyperchloremic acidosis, except in patients who have ongoing lactic acidosis, in whom the administered lactate will not be metabolized.
The rate of crystalloid administration cannot be derived from empirical formulas. In general, crystalloid may be administered at a rate 50–100 mL/hour greater than ongoing losses, unless the patient is profoundly depleted. For patients who are profoundly hypotensive or in septic shock, a goal-directed approach that combines early central venous pressure (CVP) monitoring with crystalloid administration to maintain the CVP at 8–12 mm Hg has been shown to improve outcomes. Repeated 500-mL boluses of crystalloid can be given every 30 minutes to achieve a CVP of 8–12 mm Hg. One exception to this rule is for patients who are bleeding. In this situation, blood products rather than crystalloids are recommended, with the goal of increasing the hematocrit up to a maximum of 35%. Values above this are associated with potential complications.
When ECF volume depletion is persistent, owing to ongoing renal losses, maneuvers to reduce those losses or to supplement intake are useful. Ingestion of a high salt diet or the use of the synthetic mineralocorticoid, fludrocortisone, may be useful to treat patients with inherited or acquired salt-wasting disorders.
The prognosis of hypovolemia is usually excellent, as long as corrective maneuvers are instituted promptly. Most authorities attribute substantial reductions in childhood mortality to the use of oral rehydration solutions to treat infectious diarrhea in developing countries.
