Physiology 5th Ed.


Water is the medium of the internal environment and constitutes a large percentage of the body weight. Discussion in this section includes the distribution of water in various compartments of the body; the methods of measuring volumes of the body fluid compartments; the differences in concentrations of major cations and anions among the compartments; and the shifts of water that occur between the body fluid compartments when a physiologic disturbance occurs.

Distribution of Water among the Body Fluids

Total Body Water

Water accounts for 50% to 70% of body weight, with an average value of 60% (Fig. 6-4). The percentage of total body water varies, depending on gender and the amount of adipose tissue in the body. Water content of the body correlates inversely with fat content. Women have lower percentages of water than men (because women have the higher percentage of adipose tissue). For these reasons, thin men have the highest percentage of body weight as water (≈70%) and obese women have the lowest percentage (≈50%).


Figure 6–4 Body fluid compartments. Total body water is distributed between intracellular fluid and extracellular fluid. Water as a percentage of body weight is indicated for the major compartments.

The relationship between water content and body weight is clinically important because changes in body weight can be used to estimate changes in body water content. For example, in the absence of other explanations, a sudden weight loss of 3 kg reflects a loss of 3 kg (≈3 L) of total body water.

The distribution of water among the body fluid compartments is shown in Figure 6-4. Total body water is distributed between two major compartments: intracellular fluid (ICF) and extracellular fluid(ECF). Approximately two thirds of total body water is in the ICF, and about one third is in the ECF. When expressed as percentage of body weight, 40% of body weight is in ICF (two thirds of 60%), and 20% of body weight is in ECF (one third of 60%). (The 60-40-20 rule is useful to know: 60% of body weight is water, 40% is ICF, and 20% is ECF.) ECF is further divided among two minor compartments: the interstitial fluid and the plasma. Approximately three fourths of the ECF is found in the interstitial compartment, and the remaining one fourth is found in the plasma. A third body fluid compartment, thetranscellular compartment (not shown in Fig. 6-4), is quantitatively small and includes the cerebrospinal, pleural, peritoneal, and digestive fluids.

Intracellular Fluid

ICF is the water inside the cells in which all intracellular solutes are dissolved. It constitutes two thirds of total body water or 40% of body weight. The composition of ICF is discussed in Chapter 1. Briefly, the major cations are potassium (K+) and magnesium (Mg2+), and the major anions are proteins and organic phosphates such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP).

Extracellular Fluid

ECF is the water outside the cells. It constitutes one third of total body water or 20% of body weight. ECF is divided among two subcompartments: plasma and interstitial fluid. Plasma is the fluid that circulates in the blood vessels, and interstitial fluid bathes the cells. The composition of ECF differs substantially from ICF: The major cation of ECF is sodium (Na+), and the major anions are chloride (Cl) and bicarbonate (HCO3).

Plasma is the aqueous component of blood. It is the fluid in which the blood cells are suspended. On a volume basis, plasma constitutes 55% of blood volume and blood cells (i.e., red blood cells, white blood cells, and platelets) constitute the remaining 45% of blood volume. The percent of blood volume occupied by red blood cells is called the hematocrit, which averages 0.45 or 45% and is higher in males (0.48) than in females (0.42). Plasma proteinsconstitute about 7% of plasma by volume; thus, only 93% of plasma volume is plasma water, a correction that usually is ignored.

Interstitial fluid is an ultrafiltrate of plasma: It has nearly the same composition as plasma, excluding plasma proteins and blood cells. To understand why interstitial fluid contains little protein and no blood cells, simply remember that it is formed by filtration across capillary walls (see Chapter 4). Pores in the capillary wall permit free passage of water and small solutes, but these pores are not large enough to permit passage of large protein molecules or cells. There are also small differences in the concentrations of small cations and anions between interstitial fluid and plasma, explained by the Gibbs-Donnan effect of the negatively charged plasma proteins (see Chapter 1). The Gibbs-Donnan effect predicts that plasma will have a slightly higher concentration of small cations (e.g., Na+) than interstitial fluid and a slightly lower concentration of small anions (e.g., Cl).

Measuring Volumes of Body Fluid Compartments

In humans, the volumes of the body fluid compartments are measured by the dilution method. The basic principle underlying this method is that a marker substance will be distributed in the body fluid compartments according to its physical characteristics. For example, a large molecular weight sugar such as mannitol cannot cross cell membranes and it will be distributed in ECF but not in ICF. Thus, mannitol is a marker for ECF volume. In contrast, isotopic water (e.g., D2O) will be distributed everywhere that water is distributed and it is used as a marker for total body water.

The following steps are used to measure volumes of body fluid compartments by the dilution method:

1.          Identification of an appropriate marker substance. The markers are selected according to their physical characteristics (Table 6-1). The markers for total body water are substances that are distributed wherever water is found. These substances include isotopic water (e.g., D2O and tritiated water [THO]) and antipyrine, a substance that is lipid soluble. The markers for ECF volume are substances that distribute throughout the ECF but do not cross cell membranes. These substances include large molecular weight sugars such as mannitol and inulin and large molecular weight anions such as sulfate. Markers for plasma volume are substances that distribute in plasma but not in interstitial fluid, because they are too large to cross capillary walls. These substances include radioactive albumin and Evans blue, a dye that binds to albumin.

Table 6–1 Summary of Body Fluid Compartments


D2O, Deuterium oxide; ECF, extracellular fluid; ICF, intracellular fluid; TBW, total body water; THO, tritiated water.

*Range of normal values for total body water is 50% to 70% of body weight.

ICF and interstitial fluid volumes cannot be measured directly because there are no unique markers for these compartments. Hence, ICF volume and interstitial fluid volume are determined indirectly. ICF volume is the difference between total body water and ECF volume. Interstitial fluid volume is the difference between ECF volume and plasma volume.

2.          Injection of a known amount of the marker substance. The amount of marker substance injected into the blood is measured in milligrams (mg), millimoles (mmol), or units of radioactivity (e.g., millicuries [mCi]).

3.          Equilibration and measurement of plasma concentration. The marker is allowed to equilibrate in the body fluids, correction is made for any urinary losses during the equilibration period, and the concentration of the marker is then measured in plasma.

4.          Calculation of the volume of the body fluid compartment. Because the amount of marker present in the body is known (i.e., the difference between the amount originally injected and the amount excreted in urine) and the concentration is measured, the volume of distribution of the marker substance can be calculated as follows:




= Volume of distribution (L)




Volume of body fluid

compartment (L)


= Amount of marker injected

- Amount excreted (mg)


= Concentration in plasma (mg/L)

SAMPLE PROBLEM. A 65-kg man is participating in a research study for which it is necessary to know the volumes of his body fluid compartments. To measure these volumes, the man is injected with 100 mCi of D2O and 500 mg of mannitol. During a 2-hour equilibration period, he excretes 10% of the D2O and 10% of the mannitol in his urine. Following equilibration, the concentration of D2O in plasma is 0.213 mCi/100 mL and the concentration of mannitol is 3.2 mg/100 mL. What is his total body water, his ECF volume, and his ICF volume? Is the man’s total body water appropriate for his weight?

SOLUTION. Total body water can be calculated from the volume of distribution of D2O, and ECF volume can be calculated from the volume of distribution of mannitol. ICF volume cannot be measured directly, but it can be calculated as the difference between total body water and ECF volume.



The man’s total body water is 42.3 L, which is 65.1% of his body weight (42.3 L is approximately 42.3 kg; 42.3 kg/65 kg = 65.1%). This percentage falls within the normal range of 50% to 70% of body weight.

Shifts of Water between Body Fluid Compartments

The normal distribution of total body water is described earlier in this chapter and in Chapter 1. There are, however, a number of disturbances that, by altering solute or water balance, cause a shift of waterbetween the body fluid compartments. Among the disturbances to be considered are diarrhea, severe dehydration, adrenal insufficiency, infusion of isotonic saline, high sodium chloride (NaCl) intake, and syndrome of inappropriate antidiuretic hormone (SIADH). This section provides a systematic approach to understanding common disturbances of fluid balance.

The following key principles are necessary to understand fluid shifts between the body fluid compartments. Learn and understand these principles!

1.          The volume of a body fluid compartment depends on the amount of solute it contains. For example, the volume of the ECF is determined by its total solute content. Because the major cation of ECF is Na+ (and its accompanying anions Cl and HCO3), ECF volume is determined by the amount of NaCl and sodium bicarbonate (NaHCO3) it contains.

2.          Osmolarity is the concentration of osmotically active particles, expressed as milliosmoles per liter (mOsm/L). In practice, osmolarity is the same as osmolality (mOsm/kgH2O) because 1 L of water is equivalent to 1 kg of water. The normal value for osmolarity of the body fluids is 290 mOsm/L, or, for simplicity, 300 mOsm/L.

  Plasma osmolarity can be estimated from the plasma Na+ concentration, plasma glucose concentration, and blood urea nitrogen (BUN), as these are the major solutes of ECF and plasma.



Plasma osmolarity

= Plasma osmolarity (total osmolar concentration) in mOsm/L


= Plasma Na+ concentration in mEq/L


= Plasma glucose concentration in mg/dL


= Blood urea nitrogen concentration in mg/dL

The Na+ concentration is multiplied by 2 because Na+ must be balanced by an equal concentration of anions. (In plasma, these anions are Cl and HCO3.) The glucose concentration in mg/dL is converted to mOsm/L when it is divided by 18. The BUN in mg/dL is converted to mOsm/L when it is divided by 2.8.

3.          In the steady state, intracellular osmolarity is equal to extracellular osmolarity. In other words, osmolarity is the same throughout the body fluids. To maintain this equality, water shifts freely across cell membranes. Thus, if a disturbance occurs to change the ECF osmolarity, water will shift across cell membranes to make the ICF osmolarity equal to the new ECF osmolarity. After a brief period of equilibration (while the shift of water occurs), a new steady state will be achieved and the osmolarities again will be equal.

4.          Solutes such as NaCl and NaHCO3 and large sugars such as mannitol are assumed to be confined to the ECF compartment because they do not readily cross cell membranes. For example, if a person ingests a large quantity of NaCl, that NaCl will be added only to the ECF compartment and the total solute content of the ECF will be increased.

Six disturbances of body fluids are summarized in Table 6-2 and are illustrated in Figure 6-5. The disturbances are grouped and named according to whether they involve volume contraction or volume expansion and whether they involve an increase or a decrease in body fluid osmolarity.

Table 6–2 Disturbances of Body Fluids


ECF, Extracellular fluid; ICF, intracellular fluid; NaCl, sodium chloride; N.C., no change; SIADH, syndrome of inappropriate antidiuretic hormone.


Figure 6–5 Shifts of water between body fluid compartments. Normal extracellular fluid (ECF) and intracellular fluid (ICF) osmolarity are shown by solid lines. Changes in volume and osmolarity in response to various disturbances are shown by dashed lines. SIADH, Syndrome of inappropriate antidiuretic hormone.

Volume contraction means a decrease in ECF volume. Volume expansion means an increase in ECF volume. The terms isosmotic, hyperosmotic, and hyposmotic refer to the osmolarity of the ECF. Thus, anisosmoticdisturbance means that there is no change in ECF osmolarity; a hyperosmotic disturbance means that there has been an increase in ECF osmolarity; and a hyposmotic disturbance means that there has been a decrease in ECF osmolarity.

To understand the events that occur in these disturbances, a three-step approach should be used. First, identify any change occurring in the ECF (e.g., Was solute added to the ECF? Was water lost from the ECF?). Second, decide whether that change will produce an increase, a decrease, or no change in ECF osmolarity. Third, if there is a change in ECF osmolarity, determine whether water will shift into or out of the cells to reestablish equality between ECF osmolarity and ICF osmolarity. If there is no change in ECF osmolarity, no water shift will occur. If there is a change in ECF osmolarity, then a water shift must occur.

Isosmotic Volume Contraction—Diarrhea

A person with diarrhea loses a large volume of fluid from the gastrointestinal tract. The osmolarity of the fluid lost is approximately equal to that of the ECF—it is isosmotic. Thus, the disturbance in diarrhea is loss of isosmotic fluidfrom ECF. As a result, ECF volume decreases, but there is no accompanying change in ECF osmolarity (because the fluid that was lost is isosmotic). Because there is no change in ECF osmolarity, there is no need for a fluid shift across cell membranes and ICF volume remains unchanged. In the new steady state, ECF volume decreases and the osmolarities of ECF and ICF are unchanged. The decrease in ECF volume means that blood volume (a component of ECF) also is reduced, which produces a decrease in arterial pressure.

Other consequences of diarrhea include increased hematocrit and increased plasma protein concentration, which are explained by the loss of isosmotic fluid from the ECF compartment. The red blood cells and proteins that remain behind in the vascular component of the ECF are concentrated by this fluid loss.

Hyperosmotic Volume Contraction—Water Deprivation

A person who is lost in the desert without adequate drinking water loses both NaCl and water in sweat. A key piece of information, not immediately obvious, is that sweat is hyposmotic relative to ECF; that is, compared with the body fluids, sweat contains relatively more water than solute. Because hyposmotic fluid is lost from the ECF, ECF volume decreases and ECF osmolarity increases. ECF osmolarity is transiently higher than ICF osmolarity, and this difference in osmolarity causes water to shift from ICF into ECF. Water will flow until ICF osmolarity increases and becomes equal to ECF osmolarity. This shift of water out of cells decreases ICF volume. In the new steady state, both ECF and ICF volumes will be decreased and ECF and ICF osmolarities will be increased and equal to each other.

In hyperosmotic volume contraction, the plasma protein concentration is increased but the hematocrit is unchanged. The explanation for the increase in plasma protein concentration is straightforward: Fluid is lost from ECF, and the plasma protein remaining behind becomes concentrated. It is less obvious, however, why the hematocrit is unchanged. Loss of fluid from ECF alone would cause an increase in the concentration of red blood cells and an increase in hematocrit. However, there also is a fluid shift in this disturbance: Water moves from ICF to ECF. Because red blood cells are cells, water shifts out of them, decreasing their volume. Thus, the concentration of red blood cells increases, but red blood cell volume decreases. The two effects offset each other, and hematocrit is unchanged.

What is the final state of the ECF volume? Is it decreased (because of the loss of ECF volume in sweat), increased (because of the water shift from ICF to ECF), or unchanged (because both occur)? Figure 6-5 shows that ECF volume is lower than normal, but why? Determining the ECF volume in the new steady state is complicated because, although volume is lost from ECF in sweat, water also shifts from ICF to ECF. The following sample problem shows how to determine the new ECF volume to answer the questions posed:

SAMPLE PROBLEM. A woman runs a marathon on a hot September day and drinks no fluids to replace the volumes lost in sweat. It is determined that she lost 3 L of sweat, which had an osmolarity of 150 mOsm/L. Before the marathon, her total body water was 36 L, her ECF volume was 12 L, her ICF volume was 24 L, and her body fluid osmolarity was 300 mOsm/L. Assume that a new steady state is achieved and that all of the solute (i.e., NaCl) lost from her body came from the ECF. What is her ECF volume and osmolarity after the marathon?

SOLUTION. Values before the marathon will be called old, and values after the marathon will be called new. To solve this problem, first calculate the new osmolarity because osmolarity will be the same throughout the body fluids in the new steady state. Then calculate the new ECF volume using the new osmolarity.

To calculate the new osmolarity, calculate the total number of osmoles in the body after the fluid is lost in sweat (New osmoles = Old osmoles − Osmoles lost in sweat). Then divide the new osmoles by the new total body water to obtain the new osmolarity. (Remember that the new total body water is 36 L minus the 3 L lost in sweat.)





To calculate the new ECF volume, assume that all of the solute (NaCl) lost in sweat comes from the ECF. Calculate the new ECF osmoles after this loss, then divide by the new osmolarity (previously calculated) to obtain the new ECF volume.




To summarize the calculations in this example, after the marathon the ECF osmolarity increases to 313.6 mOsm/L because a hyposmotic solution is lost from the body (i.e., relatively more water than solute was lost in sweat). After the marathon, the ECF volume decreases to 10 L (from the original 12 L). Therefore, some, but not all, of the ECF volume lost in sweat was replaced by the shift of water from ICF to ECF. Had there been no shift of water, then the new ECF volume would have been even lower (i.e., 9 L).

Hyposmotic Volume Contraction—Adrenal Insufficiency

A person with adrenal insufficiency has a deficiency of several hormones including aldosterone, a hormone that normally promotes Na+ reabsorption in the distal tubule and collecting ducts. As a result ofaldosterone deficiency,excess NaCl is excreted in the urine. Because NaCl is an ECF solute, ECF osmolarity decreases. Transiently, ECF osmolarity is less than ICF osmolarity, which causes water to shift from ECF to ICF until ICF osmolarity decreases to the same level as ECF osmolarity. In the new steady state, both ECF and ICF osmolarities will be lower than normal and equal to each other. Because of the shift of water, ECF volume will be decreased and ICF volume will be increased.

In hyposmotic volume contraction, both plasma protein concentration and hematocrit will be increased because of the decrease in ECF volume. Hematocrit increases also because of the shift of water into red blood cells, increasing cell volume.

Isosmotic Volume Expansion—Infusion of NaCl

A person who receives an infusion of isotonic NaCl presents the opposite clinical picture of the person who has lost isotonic fluid through diarrhea. Because NaCl is an extracellular solute, all of the isotonic NaCl solution is added to the ECF, causing an increase in ECF volume but no change in ECF osmolarity. There will be no shift of water between ICF and ECF because there is no difference in osmolarity between the two compartments. Both plasma protein concentration and hematocrit will decrease (i.e., be diluted) because of the increase in ECF volume.

Hyperosmotic Volume Expansion—High NaCl Intake

Ingesting dry NaCl (e.g., eating a bag of potato chips) will increase the total amount of solute in the ECF. As a result, ECF osmolarity increases. Transiently, ECF osmolarity is higher than ICF osmolarity, which causes water to shift from ICF to ECF, decreasing ICF volume and increasing ECF volume. In the new steady state, both ECF and ICF osmolarities will be higher than normal and equal to each other. Because of the shift of water out of cells, ICF volume will decrease and ECF volume will increase.

In hyperosmotic volume expansion, both plasma protein concentration and hematocrit will decrease due to the increase in ECF volume. Hematocrit also will be decreased because of the water shift out of the red blood cells.

Hyposmotic Volume Expansion—SIADH

A person with syndrome of inappropriate antidiuretic hormone (SIADH) secretes inappropriately high levels of antidiuretic hormone (ADH), which promotes water reabsorption in the collecting ducts. When ADH levels are abnormally high, too much water is reabsorbed and the excess water is retained and distributed throughout the total body water. The volume of water that is added to ECF and ICF is in direct proportion to their original volumes. For example, if an extra 3 L of water is reabsorbed by the collecting ducts, 1 L will be added to the ECF and 2 L will be added to the ICF (because ECF constitutes one third and ICF constitutes two thirds of the total body water). When compared with the normal state, ECF and ICF volumes will be increased and ECF and ICF osmolarities will be decreased.

In hyposmotic volume expansion, plasma protein concentration is decreased by dilution. However, the hematocrit is unchanged as a result of two offsetting effects: The concentration of red blood cells decreases because of dilution, but red blood cell volume increases because water shifts into the cells.