Language Guiding Therapy: The Case of Dehydration versus Volume Depletion

  1. Kevin Mange, MD;
  2. Dean Matsuura, MD;
  3. Borut Cizman, MD;
  4. Haydee Soto, MD;
  5. Fuad N. Ziyadeh, MD;
  6. Stanley Goldfarb, MD; and
  7. Eric G. Neilson, MD
  1. University of Pennsylvania Philadelphia, PA 19104 Grant Support: In part by grant DK-07006 from the National Institutes of Health and by the DCI RED fund. Drs. Mange, Matsuura, Cizman, and Soto are first-year renal fellows in the Renal-Electrolyte and Hypertension Division. Requests for Reprints: Eric G. Neilson, MD, Renal-Electrolyte and Hypertension Division, 700 Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144. Current Author Addresses: Drs. Mange, Matsuura, Cizman, Soto, Ziyadeh, Goldfarb, and Neilson: Renal-Electrolyte and Hypertension Division, 700 Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144. Acknowledgments: The authors thank Dr. Richard Tannen, Professor and Vice-Dean for Research at the University of Pennsylvania, for critically reading this manuscript. Current Author Addresses: Drs. Mange, Matsuura, Cizman, Soto, Ziyadeh, Goldfarb, and Neilson: Renal-Electrolyte and Hypertension Division, 700 Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144.

    Patients presenting with orthostatic hypotension and normal plasma sodium concentrations are frequently admitted to the hospital with a diagnosis of dehydration. If they are fortunate, they receive fluids containing sodium chloride instead of free water to correct obvious extracellular fluid volume depletion. Confusing this diagnosis highlights the growing and pernicious habit of using the terms dehydration and volume depletion interchangeably at the bedside when the two describe clearly different disturbances.

    The heuristic value of describing discrete body fluid spaces affected by disorders of salt and water is a well-established bedside strategy [1-5]. It sprang from an early curiosity about the best treatment for fatal diarrhea [6] and seizures [7] and from classic experiments that formulated the volume behavior and osmolarity of cells [8, 9]. Adapting this information from cells to humans in the late 1930s required more conceptual thinking about the special role of vascular volume in the control of body fluids [2, 10]. The wartime assessment of potential fluid losses encountered by shipwrecked aviators and sailors in the early 1940s further enhanced our understanding of salt and water metabolism [11-13], as did the emerging role of cardiac performance [14, 15].

    With the advent of radioactive tracers [16, 17], medical language in the latter part of the 20th century began to discriminate more carefully between dehydration associated with hypertonicity, a principal loss of body water from the intracellular and interstitial compartments, and extracellular fluid volume depletion, a fluid deficiency that clinically affects the vascular tree [3, 5, 18]. The proper use of the terms dehydration and volume depletion informs communication and should improve patient care.

     
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    The Language of Salt and Water in Body Fluid Spaces

    At steady state, the hydration or water content of body fluids represents a physiologic balance achieved by the ingestion of water and its further distribution, evaporation, and clearance by the kidneys and gut [19, 20]. Total body water disperses in a well-defined pattern [8, 21, 22] across several elastic or “virtual” spaces [1, 3, 5, 22]. Approximately 66% of water is confined by solute to the intracellular compartment, whereas 33% is found in the extracellular space. Only 25% of this extracellular fluid, or 8% of total body water, resides within the vasculature [1, 4, 17], and eventually all spaces achieve identical osmolarity [23].

    The concept of osmotic pressure derives from the fundamental gas laws of physical chemistry [2, 24]. Water moves down a concentration gradient generated by the osmotic properties of solutes bound by a semipermeable membrane to achieve equilibrium [2]. Simple osmosis of water across virtual body compartments is further amended by the Gibbs-Donnan effect of charge-bearing proteins [2] and, in blood vessels, by the hydrostatic attributes of Starling forces [10, 25]. Although measured osmolarity reflects all particles per volume of water, not all osmols influence transmembrane water flow [5].

    The power to move water across cell membranes is a property of “effective” osmols [2, 26, 27]. Tonicity describes the volume behavior of such cells in solution and is modulated by the number of effective osmols, or osmotically active particles, that are restricted to one side of the cell membrane because of permeability characteristics, transmembrane pumps, or both [28]. Most effective osmols are extracellular sodium, chloride, and bicarbonate or intracellular potassium, chloride, and phosphate. Less abundant effective osmols are sugars, lipids, and proteins. Solutes such as urea or alcohol, however, freely move across cell membranes and are therefore ineffective osmols unable to effect transmembrane water flow [26].

    Acutely, effective osmols in the intracellular space (particularly potassium salts) are relatively fixed, and thus the major influence on the location of water in this space is the effective osmolarity of the extracellular compartment [3, 26]. When water is lost from the skin, gut, or kidneys, the hypertonicity created in the extracellular space is directly transferred to the larger intracellular space [5]. Worsening hypertonicity therefore has its biggest impact on the size of the intracellular compartment and, to a lesser extent, on interstitial spaces. To dehydrate is to lose this intracellular water and stimulate thirst.

    The physiologic concept of dehydration, at first glance, might subsume the definition of volume depletion. This erroneous assumption, made by investigators early in this century [26, 29], was corrected by physiologists in the era after World War II [3, 18, 30] but today has insidiously resurfaced because volume depletion has become a shorthand for extracellular fluid volume depletion, and the first two words of the latter phrase make all the difference.

    The volume of the extracellular fluid space is principally regulated by the ingestion and excretion of sodium salts [31]. Sodium is largely confined to extracellular fluid because cell membrane pumps operate to actively exclude it from the intracellular compartment [28, 32]. Thus, the addition of sodium leads to a specific gain of effective osmols in extracellular spaces. If sodium is added isotonically to the extracellular compartment, no shift of water from the intracellular space will ensue and the volume increase of the extracellular space will equal the volume of isotonic infusate. If hypotonic or hypertonic sodium is added to the extracellular space, the volume of the intracellular space changes accordingly [26, 29].

    Changes in extracellular volume can therefore be dissociated from changes in intracellular volume [5, 21, 33]. For example, a patient who bleeds will have a rapid decline in vascular volume but, in the absence of tissue injury or change in extracellular tonicity, will not have redistribution of water from intracellular spaces [3, 34]. Such a person will have a deficit of body water equal to the proportionately small water content of the lost blood. This can be illustrated quantitatively by considering the fate of an administrated infusate of 5% dextrose compared with an equal volume of fluid given as 0.9% saline (Table 1). Both infusates provide equal amounts of water, but their effect on plasma volume is vastly different.

    View this table:
    Table 1. Effect of a 1-L Infusion of Water or 0.9% Saline on Virtual Body Fluid Spaces
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    Assessment of Body Fluid Spaces in Designing Effective Therapies

    Dehydration

    To best assess the state of hydration, one needs to ascertain the concentration of a marker substance whose content is constant and whose distribution is uniform throughout all virtual fluid spaces. Of course, surrogate markers were devised because no such natural substance exists [16]. Because sodium is the most abundant extracellular solute and its concentration (p[Na+]) influences water movement across cells, p[Na+] may be used as a surrogate at the bedside to gauge the relation between water and effective osmols in all body fluids [5]. Although anions and large molecules contribute to the property of tonicity, some intracellular anions are complex moieties that are not easy to formulate in simple terms; therefore, it is more convenient to estimate effective osmols in a representational shorthand that consists of cations. Equation 1 Formula [1] provides a conceptual framework with which to predict relative water deficit or excess determining tonicity [30]: (Equation 1) where TBNa+ is total body sodium, TBK+ is total body potassium, TBH2O is total body water, CM is cell membrane, ECH (2) O is extracellular water, and ICH2O is intracellular water. In this formula, extracellular total body sodium and intracellular total body potassium represent the principal effective osmols that partition total body water (0.6 L/kg of body weight in adult men and 0.5 L/kg in adult women) across cell membranes at equilibrium [21, 23, 27, 35].

    Formula

    The signs and symptoms of acute dehydration are thirst and, progressively, confusion, coma, and respiratory paralysis [28]. These complications may be mitigated if hypertonicity develops over time and if the brain and other tissues are allowed to adapt by generating new intracellular solutes (previously called idiogenic osmols) to minimize shrinkage [33, 36]. These new solutes include sodium chloride, amino acids, myoinositol, and methylamines [37, 38].

    Isolated water deficits are corrected by water replacement and can be estimated [30], over and above any isotonic change in extracellular volume, by using Equation 8 formula [5] (for the derivation of Equation 8 formula [5], see Appendix): (Equation 2)

    Formula Formula

    The presentation of dehydration is well illustrated by the case of an elderly 70-kg woman with bipolar disorder and angina who was receiving lithium therapy and was admitted after a positive stress test result. Her blood pressure was 128/85 mm Hg, and her heart rate was 82 beats/min. Evaluation was unremarkable except for thirst and a p[Na+] of 150 mEq/L. Without orthostasis or evidence of decreased tissue perfusion, the patient was given a diagnosis of hypertonicity brought on by acute water deprivation superimposed on lithium-induced nephrogenic diabetes insipidus. She required intravenous water expansion with 5% dextrose before cardiac catheterization because the dye load and ensuing osmotic diuresis would have worsened the hypertonicity by producing urine with lower concentrations of sodium and potassium than are found in body fluids [39].

    Assuming the expected restoration of p[Na+] to 140 mEq/L, the patient's free water deficit was calculated by using Equation 8 formula [5], as follows: (Equation 3)

    Formula

    In addition, any urine output during treatment should be replaced in the same ratio of solute (sodium plus potassium) to water. If the patient's condition had actually been mislabeled as extracellular fluid volume depletion and 0.9% saline (154 mEq of Na+/L) had been administered instead of 5% dextrose, p[Na+] would have increased to (Equation 4) leaving the tonicity slightly worse and possibly expanding the extracellular fluid volume beyond the tolerance of her cardiac function. The choice of fluid in this case is dictated by the correct diagnosis of dehydration.

    Formula

    Volume Depletion

    Extracellular fluid volume depletion is precipitated by blood loss, a net reduction in total body sodium content, or both. Patients with this condition are often light-headed and orthostatic as a result of reduced effective circulatory blood volume [38, 39]. The steady-state content of extracellular sodium regulating volume is modulated by the kidneys in response to a variety of sensing and effector mechanisms [40-50], which lead to neurohormonal and intrarenal hemodynamic changes that control urinary sodium. There are no normal values for urinary sodium or potassium excretion because these urinary solutes tend to equal dietary intake at a steady state termed euvolemia [51, 52]. When extracellular volume is depleted by 10% to 15%, renal hypoperfusion may lead to oliguria with intense conservation of sodium and water [31, 44].

    Renal sodium handling is modulated by the state of the extracellular fluid volume or, more conceptually, the fullness of the circulation [9]. If the circulation is too full, the renal reabsorption of sodium rapidly decreases to restore the initial circulatory set point. If the fullness of the circulation, particularly the arterial circulation [53], is sensed to be reduced, then renal conservation of sodium and water is enhanced. Sodium and not pure water retention is most crucial for the repair of circulatory volume because retention of water without sodium chloride will have a marginal effect on the size of the intravascular volume (Table 1).

    This is illustrated by the case of a middle-aged man admitted to the hospital for extensive watery diarrhea after returning from Mexico. He had been self-treating at home with juices until nausea set in. On examination, he was weak with postural hypotension, a p[Na+] of 137 mEq/L, and a p[K+] of 3.7 mEq/L. His weight had decreased from 70 to 66 kg, and his bladder was empty except for a small amount of urine with an osmolarity of 670 mOsm/L, a Na+ concentration of 5 mEq/L, and a K+ concentration of 60 mEq/L. Stool electrolyte studies revealed a Na+ concentration of 103 mEq/L and a K+ concentration of 35 mEq/L.

    This patient's diarrhea and self-ministrations had produced near-isotonic losses of solute with extracellular fluid volume depletion. The patient was treated with antibiotics for Vibrio cholerae and was given fluids to restore extracellular volume. A loss of 4 L of isotonic fluids was replaced with 0.9% saline to improve tissue perfusion. The resultant p[Na+] was as follows: (Equation 5)

    Formula

    Administration of oral fluids was restarted shortly thereafter.

    Dehydration and Volume Depletion

    Fluid homeostasis normally operates to preserve tissue perfusion first and tonicity second [54, 55]. Orthostatic decreases in blood pressure that are not due to neurologic disorders, deconditioning, or sepsis almost always imply sodium deficits. Furthermore, it is very difficult to develop severe extracellular fluid volume depletion during a pure state of dehydration because, although water deficits are shared proportionally by all compartments, 92% of the water losses are intracellular and interstitial and, unless massive, do not significantly modulate volume receptors. The vascular compartment in this case is also reduced, but the increase in oncotic pressure from concentrated plasma proteins further protects the small 8% reduction in circulatory volume [30]. To realize extracellular volume depletion equal to that achieved by a loss of 1 L of blood would require the loss of approximately 12 L of pure water across the total body water. Of course, dehydration and volume depletion can occur together. Because each is treated differently and at a different rate (slow for dehydration and rapid for volume depletion), it is essential to recognize their separate characteristics in correcting complex fluid and electrolyte disturbances.

    For example, a 70-year-old woman with diabetes was admitted to the hospital from a nursing home for change in mental status. Her caregiver had been withholding insulin because she had stopped eating. On examination, she was comatose and weighed 50 kg. She had a palpable blood pressure of 80 mm Hg while supine, a body temperature of 38.3 °C, poor skin turgor, dry mucous membranes, and foul-smelling urine. She had a p[Na+] of 175 mEq/L, a p[K+] of 3.8 mEq/L, a p[Cl-] of 139 mEq/L, a p[HCO3-] of 23 mEq/L, a urea nitrogen concentration of 65 mg/dL, a creatinine concentration of 2.8 mg/dL, and a glucose concentration of 1260 mg/dL.

    The patient was given a diagnosis of hyperosmolar, hyperglycemic, nonketotic diabetic coma [56]. She had had substantial loss of total body sodium from glucose-induced osmotic diuresis, which had led to circulatory compromise [39]. In addition, her water deficits and hypertonicity had been aggravated by an inability to drink fluids to correct ongoing hypotonic losses. Her hypotension demanded immediate volume resuscitation and treatment for presumed sepsis.

    The patient's tonicity on admission was estimated to be at least 420 mOsm/L, of which 70 mOsm/L was attributable to her elevated blood glucose concentration. Hypertonicity of this magnitude is life-threatening and may be associated with early brain cell shrinkage followed by a complex reequilibration [36, 56, 57]. The patient's water deficits were far worse than her p[Na+] of 175 mEq suggested because for every 100 mg/dL increase in the plasma glucose concentration, there is a reduction in p[Na (+)] of 1.6 mEq/L, caused by the redistribution of intracellular water to the extracellular fluid [58]. If her glucose concentration were not increased, the p[Na+] would correct to the following: (Equation 6)

    Formula

    This blood glucose level should be decreased with insulin, but this should not be done so quickly that extracellular fluid volume is reduced before some saline has been administered.

    The fluid management strategy was staged to first restore blood pressure. If hypotension was due principally to fluid losses and not septicemia, the patient would need an initial infusion of 0.9% saline to increase extracellular volume. Although the magnitude of the patient's volume deficit cannot be predicted with great precision, it is at least 10% to 15% of body weight: (Equation 7)

    Formula

    Bedside examination and reassessment of ongoing fluid and solute losses is the best guide to how much additional saline the patient should be given once this first estimate is reached. Saline here will also gradually decrease tonicity because its osmolarity is hypotonic to the patient's current state, and volume expansion will promote glycosuria. Potassium is added to the replacement fluid after urine output is restored and before too much glucose and potassium are driven back into cells with insulin.

    In the second stage of fluid therapy, the patient needs to have her water deficit corrected gradually according to Equation 8 formula [5]:

    The rate for this correction is usually factored empirically against the duration of hypertonicity, in recognition of the fact that the patient's brain can swell when dehydration is corrected too rapidly [33, 36, 57, 59].

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    Summary

    Indiscriminate use of the terms dehydration and volume depletion, so carefully crafted by our predecessors, risks confusion and therapeutic errors. These two conditions should be distinguished at the bedside and in how we speak to one another. Dehydration largely refers to intracellular water deficits stemming from hypertonicity and a disturbance in water metabolism. The diagnosis of dehydration cannot be established without laboratory analysis of p[Na+] or calculation of serum tonicity. In contrast, volume depletion describes the net loss of total body sodium and a reduction in intravascular volume and is best termed extracellular fluid volume depletion. The diagnosis of this condition relies principally on history, careful physical examination, and adjunctive data from laboratory studies.

    The pathophysiology of both dehydration and extracellular fluid volume depletion must be understood if these conditions are to be recognized and appropriately treated when they occur separately or together. There is no inclusive therapy for all situations. For example, indiscriminate treatment with 0.45% saline cannot be recommended when these conditions coexist because extracellular fluid volume depletion is often treated rapidly with 0.9% saline and dehydration is often treated more slowly with 5% dextrose.

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    Appendix

    The derivation of formula [5] is as follows: (Equation 9), (Equation 10), (Equation 11), (Equation 12), (Equation 13), (Equation 14), (Equation 15), (Equation 16)

    Formula Formula Formula Formula Formula Formula Formula Formula

    Kevin Mange, MD

    Dean Matsuura, MD

    Borut Cizman, MD

    Haydee Soto, MD

    Fuad N. Ziyadeh, MD

    Stanley Goldfarb, MD

    Eric G. Neilson, MD

    University of Pennsylvania Philadelphia, PA 19104

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