Nephrology Hypertension

Diseases of Volume Regulation: Volume Depletion

Does this patient have volume depletion?

Is this patient volume depleted?

The term "'volume," as used here, is typically shorthand for extracellular fluid volume. As the extracellular fluid is composed primarily of NaCl and water (with some NaHCO3 and some potassium), the term volume depletion typically conveys a deficiency in both NaCl and water.

Volume depletion should be differentiated from dehydration and from hypernatremia or hyponatremia. The loss of water (dehydration alone) should lead to hypernatremia. Because sodium concentration is the quotient of solute mass and fluid volume, hypernatremia and hyponatremia can both co-exist with volume depletion (when relative loss of water to sodium is high or low, or is accompanied by oral or intravenous replacement with dilute fluid).

Another term frequently employed is effective blood volume or effective arterial volume. These somewhat vague terms typically denote the volume of blood perfusing tissues. For example, in patients suffering from heart, the extracellular fluid volume is typically increased, while the effective arterial blood volume is reduced (for example, kidney perfusion can be reduced).

Typically, the physiologic control systems that regulate extracellular fluid volume (renin/angiotensin/aldosterone and sympathetic nervous system) are viewed as distinct from those regulating water balance or serum Na concentration (arginine vasopressin, countercurrent exchange). Although this is a simplification, it is a useful construct when approaching diagnosis.

The presentation of volume depletion ranges from frank shock with profound hypotension to subtle abnormalities in serum electrolyte concentrations, depending on the severity and cause.

What are disorders that lead to volume depletion?

  • A history of poor oral intake or inadequate salt intake may be present, but is usually not sufficient by itself to cause significant volume depletion.

  • Most often, losses of either extracellular fluid or blood are causes.

  • One of the most common and treatable causes is vigorous exercise, especially in hot environments.

  • A history of hemorrhage, gastrointestinal losses, or diuretic use should be sought.

  • Salt wasting is a feature of many acquired and inherited diseases

  • Renal salt wasting may occur transiently after the relief of urinary tract obstruction.

  • Intrinsic renal salt wasting may be the result of interstitial nephritis.

  • Several drugs cause salt wasting. These include the diuretics, for which salt wasting is often the desired goal, but which may deplete the volume excessively if used inappropriately.

  • Other drugs, especially antineoplastics and antibiotics can cause salt wasting is an unintended side effect.

  • Inherited salt wasting diseases include Bartter syndrome, Gitelman syndrome, and pseudohypoaldosteronism type 1.

  • A deficiency in mineralocorticoid production may result from a variety of inherited defects in steroid synthesis leading to salt wasting. Addison's disease can present as salt wasting and hypotension, especially in association with stress or surgery.

What are diagnostic clues to the presence of volume depletion?

  • In severe cases, the blood pressure may be low and tachycardia may be present.

  • in milder cases, the blood pressure will decline when the patient stands up (postural hypotension).

  • The pulse may rise abnormally when the patient stands up (postural tachycardia)

  • Thirst or salt craving may be present

  • The mucous membranes may appear dry.

  • The jugular pulse may not be visible, even when the patient is recumbent.

  • The skin turgor may be poor, but this was shown to be of little diagnostic use. Instead, dry axillae, while only 50% sensitive are 82% specific for volume depletion.

  • Specific clinical scenarios are associated with other signs, such as the hyperpigmentation of Addison disease and the hearing loss of Bartter syndrome with sensorineural deafness.

  • The volume depletion, especially when mild, may be difficult to diagnose, using history and physical exam.

What tests to perform?

  • Volume depletion is typically diagnosed on the basis of history and physical examination. Lab testing is of only secondary importance.

  • Serum electrolytes are typically obtained, and are frequently abnormal, but changes in serum sodium, potassium, chloride or even bicarbonate are not diagnostic.

  • A low serum chloride concentration and a high serum bicarbonate concentration, especially with hypokalemia, raises the likelihood of volume depletion from vomiting, Gitelman syndrome, or Bartter syndrome.

  • A hyperchloremic acidosis and hyperkalemia suggests mineralocorticoid deficiency or resistance.

  • A rise in the hemoglobin or hematocrit, or in serum albumin, suggests volume depletion, if baseline values are known.

  • A rise in the ratio of blood urea nitrogen [BUN]/creatinine may suggest volume depletion

  • Measuring the concentration of sodium in the urine (spot urine sodium) is often useful. Determination of the fractional excretion of sodium is helpful when acute kidney injury is present, but it should be recalled that the fractional sodium excretion is less than 1% in normal, nonoliguric individuals, so this test must be interpreted with caution. When a patient has been exposed to diuretics, the fractional excretion of urea may be measured, but the superiority of this approach has been questioned. When there is concomitant alkalosis, the urinary concentration of chloride may provide important information on the volume status, when the urinary Na may be elevated inappropriately by bicarbonaturia.

  • In the setting of hyponatremia, a urine Na concentration <30 mmol/L carries a high positive predictive value for the presence of volume depletion. Its value exceeds clinical assessment alone in this respect.

  • The response to a fluid challenge is often used to differentiate volume depletion from euvolemia. The type of fluid to use is discussed below. The nature of the fluid challenge is determined by the clinical situation.

  • If the volume depletion is mild, causing a decline in urine output and a rise in the BUN/creatinine ratio, then it is appropriate to correct the deficit slowly, especially in fragile patients.

  • When mild and the patient is able to eat, simply liberalizing the dietary salt intake or stopping diuretics is often both diagnostic and therapeutic. Resolution of the initial abnormalities, such as a return of the BUN or creatinine concentration to baseline, or an increase in urine output, typically confirms that volume depletion was present.

  • In contrast, if the patient is in shock or there is acute oliguria with hypotension, then a more aggressive fluid challenge is indicated, as determined by the clinical severity. In the absence of hemodynamic monitoring, a bolus of 500 ml can be administered during 30 minutes or even more quickly. After appropriate clinical evaluation, this can be repeated until hemodynamics improve.

  • In an intensive care unit (ICU) setting, where the goal may to be increase cardiace stroke volume (as part of 'early goal directed therapy') smaller bouses of 250 ml over 5-10 minutes can be repeated, with assessment of hemodynamic parameters, as discussed below.

  • A collapsing inferior vena cava, imaged by ultrasound, can indicate depletion of the extracellular fluid volume, and can be useful when bedside assessment alone is confusing.

  • A low central venous pressure (CVP) or jugular venous pressure (JVP) is consistent with volume depletion. In the setting of hypotension, it is often strongly suggestive, but when the blood pressure is normal, it holds little diagnostic use.

How should patients with volume depletion be managed?


What are the goals of fluid therapy?

The goal of fluid administration has typically been defined the correction of volume deficits, whether or not this led immediately to improvements in other parameters. Most often, an improvement in urine output or overall status is then seen as a marker of success, but these markers did not determine the need for treatment. In patients with septic shock, the concept of early goal directed therapy was studied and shown to reduce mortality. In this situation, the goal of treatment is to increase cardiac output.

Thus, it is important to define the goals of fluid therapy clearly. Of note, the goal directed approach was studied in the earliest periods of septic shock and it has been suggested that such patients need goal directed therapy early, but may need a more conservative fluid approach after than (beyond 6-12 hours of presentation).

Volume assessment in the critically ill

Special considerations apply to assessing volume status of patients in ICUs. These considerations result from both the frequent presence of multiorgan failure, and the ability to assess volume status using more sophisticated tools.

There are two major themes in ICU care that differ from those in routine settings. The first is the concept of "'early goal directed therapy, " in which volume rescussitation is designed to increase or optimize cardiac output and therefore stroke volume. In this case, successful fluid therapy is that which increases stroke volume (and thereby tissue perfusion). The second is the concept that excessive fluid administration may be detrimental to patients. These two concepts may not be mutually exclusive, as discussed below.

Controversies in assessment

The development of early "goal directed" treatment of patients with septic shock, aimed at improving tissue perfusion and oxygenation rapidly, led to different targets for fluid rescussitation than were used traditionally. In the goal directed approaches, an acute increase in stroke volume is the desired goal (to improve organ perfusion). When the need for fluid administration is defined in this way, then traditional measures, such as CVP pressure or the pulmonary artery occlusion pressure, may not predict "fluid responsiveness," at least in some studies.

Thus, other parameters have been developed that may predict fluid responsiveness better than CVP, at least when defined as noted. These include the corrected flow time (FTc), the stroke volume variability, the systolic pressure variability, the pulse pressure variability, and the response to passive leg raising. It should be noted, however, that the CVP was employed in the major randomized trial documenting the efficacy of "early goal directed therapy."

Although the goal directed approach utilizes an aggressive approach to volume resuscitation, a much more conservative approach to fluid administration in the ICU has been supported in patients with acute respiratory distress syndrome and in patients with trauma. In randomized trials, a conservative approach was associated with better outcomes. In a study of patients with acute respiratory distress syndrome in the ICU, an approach aimed in part to keep CVP <8 cm H2O was associated with shorter stays in the ICU and fewer days on ventilators. In a post hoc study of patients from the same trial who developed acute kidney injury, post AKI fluid balance was positively associated with mortality. The 'conservative' approach included more liberal use of loop diuretics.

Most investigators now suggest that aggressive fluid administration is warranted early (approximately the first 6 hours) in septic patients, or in patients with other forms of shock, to restore circulation, whereas a more conservative approach is warranted later.

One outcome of the study testing effects of conservative versus liberal fluid administration is the conclusion that prior case control studies suggesting that the use of loop diuretics adversely affected the outcome of patients with acute kidney injury likely reflected selection bias, as the use of furosemide in the conservative group did not worsen outcomes when the fluid administration was selected randomly.


For very mild volume depletion, or in patients with several salt wasting disorders, the provision of adequate NaCl intake orally is essential and may be sufficient. In the absence of disordered thirst or abnormalities of urinary concentrating capacity, fluid intake can be determined by preference.

It is often assumed that 'Sports Drinks' are a good source of NaCl, when in fact, they are salt poor. This in contrast to oral rehydration solutions, as defined by the World Health Organization, and to broth. In general, fluid deficits should be corrected at a speed that is appropriate to the clinical situation. For frank hypotension, aggressive treatment with fluids as rapidly as 1 liter in an hour (or faster, in the ICU) can be recommended. When the need is less extreme, a less aggressive approach is indicated. In each case, however, the therapeutic focus must be on serial clinical assessment to prevent volume overload.

When intravenous treatment is indicated, one of three fluids is typically chosen; normal saline, lactated Ringer's, or albumin. For massive volume replacement, lactated Ringer's reduces the likelihood of dilutional acidosis, but it contains lactate, which can increase the risk of alkalosis. Controlled trials have not shown differences in hard outcomes such as mortality, when normal saline and lactated Ringer's were compared, although intermediate variables (pH, bicarbonate, chloride concentration) may be better protected by lactated Ringer's. Recent results suggest that lactated Ringer's probably does not contribute to hyperkalemia, even when renal failure is present.

The enthusiasm for using albumin has waxed and waned over the years. Oncotic agents have theoretical benefits, but are much more expensive than crystalloids. In a very large randomized study, which compared 4% albumin with normal saline for fluid rescussitation in the ICU, there were no differenes in any of the prespecified outcomes. A recent Cochrane analysis suggested that there is little evidence for superiority of albumin and recommended its use only in tightly controlled randomized trials.

In the setting of spontaneous bacterial peritonitis, albumin use was shown to improve outcome. This has become a standard of care. Albumin is also commonly used with midodrine and octreotide to treat patients with hepatorenal syndrome, although the quality of data in support is not optimal. Albumin infusion has been shown to ameliorate post paracentesis neurohormonal surge, the rise in renin and sympathetic discharge following large volume paracentesis, but this effect has not been shown to reduce hard endpoints. On the basis of its effects during paracentesis, and on theoretical grounds, several groups now recommend that it be used to exclude the presence of pre-renal azotemia in the setting of cirrhosis, but randomized trials supporting its use are lacking.

Hydroxyethyl starch is another colloid alternative, but it has negative effects on coagulation pathways and can cause osmotic nephrosis, so it is rarely recommended. Dextrose in water and half normal saline should not be used to treat volume depletion, but they are essential to correct hypertonicity. They may be used in hypertonic volume depletion.

For patients with chronic salt wasting disorders, high NaCl intake is sometimes combined with the use of fludrocortisone, a synthetic mineralocorticoid. The diuretic medications spironolactone and amiloride are sometimes employed to treat Gitelman syndrome, despite their tendency to increase urine sodium excretion, because they can reduce potassium losses.

What happens to patients with volume depletion?

When treated appropriately,

  • Volume depleted patients recover to normal hemodynamic and renal function very quickly, in most cases.

  • Continued instability is most often the manifestation of either ongoing volume losses or supervening disorders.

How to utilize team care?


Are there clinical practice guidelines to inform decision making?

There are many guidelines for resuscitation of injured patients prior to hospitalization (see paper by Cotton et al in reference list).

Other considerations


What is the evidence?

McGee, S, Abernethy, WB, Simel, DL. "The rational clinical examination. Is this patient hypovolemic?". JAMA. vol. 281. 1999. pp. 1022-1029.

(This nicely summarizes the clincal approach to diagnosing volume depletion, as caused by hemorrhage or vomiting, diarrhea, or decreased oral intake.)

Perel, P, Roberts, I. "Colloids versus crystalloids for fluid resuscitation in crtically ill patients". Cochrane Database Syst Rev.

(This comprehensive and balanced review suggests that there are few indications fo colloid use in the intensive care unit.)


(This paper is a post hoc analysis of the data from the initial fluid balance in ARDS study. It shows that, in patients who developed AKI, mortality was lower in the group randomized to conservative fluids and diuretics)

(This is the major trial of conservative versus agressive fluid management of patients with ARDS in the intensive care unit).


(This is a balanced editorial from one of the key investigators in the goal directed trials.)


(This paper suggests that the fractional urea excretion does not add much diagnostic accuracy in patients with AKI treated with diuretics.)


(This paper suggests that, even in patients with renal failure, lactated Ringer's may be safe.)

(Follow up of SAFE study raising the possibility of albumin superiority in a subgroup with severe sepsis. It should be noted that the effect observed was quite small and that this was a subgroup analysis of a larger study that was negative, so the results should be interpreted very cautiously.)
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