Physiology, Water Balance

Cellular Level

At a cellular level, the distribution of the various fluid compartments in the body is paramount for maintaining health, function, and survival. For the average 70 kg man, 60% of the total body weight is comprised of water, equaling 42 L. The body's fluid separates into 2 main compartments: intracellular fluid volume (ICFV) and extracellular fluid volume (ECFV). 

• Of the 42 L of water in the body, two-thirds is within the intracellular fluid (ICF) space, which equates to 28 L. 
• The ECFV comprises 2 spaces: The interstitial fluid volume (ISFV) and the plasma volume (PV). One-third of the total body water is the ECFV, equivalent to 14 L. Out of the extracellular fluid volume, 75% or 10.5L of the volume is present in the interstitial space, and 25% of that water is in the plasma, equivalent to 3.5 L.[3]

Each space works in unison with the others and has different functions that are paramount for normal physiological function.

• The intracellular fluid is comprised of at least 10 separate minuscule cellular packages. For simplicity and to make the analysis of the intracellular space viable, the concept of a united intracellular “compartment” has been created. These collections have important unifying similarities such as location, composition, and behavior, which provide practical utility in studying physiology.[4]
• The interstitial fluid consists of fluid between and around bodily tissue. Although technically a “virtual” space, the interstitial fluid bathes all the cells in the body and links between intracellular fluid and the intravascular compartment. ISF contains nutrients, oxygen, waste, chemical messengers, and a small amount of protein. The ISF also contains the lymphatic system, which returns protein and excess ISF into the circulation.[5]
• Plasma is the only fluid compartment that exists as a real fluid collection all in 1 space. It differs from the interstitial fluid by its higher protein content and its function in transportation. Plasma is a component of blood and is said to be the “interstitial fluid of the blood” as it bathes the suspended red and white cells, which also reside in the blood.[6]

Mechanism

Several principles control the distribution of water between the various fluid compartments. To understand the different principles, it is essential to realize that ingestion and excretion of water and electrolytes are tightly regulated to maintain consistent total body water (TBW) and total body osmolarity (TBO). To manage these 2 parameters, body water redistributes itself to maintain a steady state so that the osmolarity of all bodily fluid compartments is identical to total body osmolarity.

Several factors mediate water redistribution between the 2 ECF compartments: hydrostatic pressure, oncotic pressure, and the osmotic force of the fluid. Combining these 2 components yields the Starling equation: Jv = Kfc [(Pc - Pi] - n (Op-Oi)].[7] This equation determines the rate of fluid across the capillary membrane (Jv). It takes the difference between the hydrostatic pressures of the capillary fluid (Pc) and the interstitial fluid (Pi), as well as the oncotic pressure of the capillary fluid (Op) and the interstitial fluid (Oi). It also considers the osmotic force between the 2 compartments (n).

Additionally, there is a relationship between the interstitial fluid and intracellular fluid. These 2 environments very closely influence each other as the cell's membrane separates them. Generally, nutrients diffuse into the cell, with waste products entering the interstitial space. Ions are typically barred from crossing the membrane but can occasionally cross via active transport or under specific conditions. Water can move freely across the membrane and is directed by the osmotic gradient between the 2 spaces. Changes in the intracellular fluid volume result from alterations in the osmolarity of the ECF but do not respond to isosmotic changes in extracellular volume.[8] However, any water flow in or out of the cell membrane has proportional changes in the ECFV. If a disturbance causes ECF osmolarity to increase, water flows out of the cell and into the extracellular space to balance the osmotic gradient; however, the total body osmolarity remains higher than what is typical, and the cell shrinks. If a disturbance were to cause a decrease in ECF osmolarity, then water would move from the ECF into the ICF to attain an osmolar equilibrium; however, the total body osmolarity would remain lower than normal, and the cell would swell. Third, if isosmotic fluid entered the extracellular space, then there would be no net changes in the ICF, and the ECFV would increase.

Related Testing

Much of this information can appear abstract, especially when talking about compartments that are more of a theoretical space. Therefore, it is crucial to have a way to measure the volumes of the different compartments physically. The way to measure the different spaces is by using the indicator-dilution method.[9] The theory behind this is that to measure the volume of a specific compartment; one must introduce measurable substances into the body that are distributed uniformly to a compartment of interest. Using this method, individual volumes can be measured directly, and others can be measured by subtracting the volumes of related compartments. This information can then be quantified by using the equation Volume (V) = Amount (substance injected)/Concentration (measured after equilibration).[10] The following compartments can be measured as follows:

• Total body water (TBW) - To measure, radioactive titrated water or antipyrine is injected. The idea behind this is that water gets uniformly distributed among all the different compartments. So, if one can measure the radioactive water, it follows you to determine the TBW.
• Extracellular fluid volume (ECFV)—To measure this volume, labeled inulin, sucrose, mannitol, or sulfate can be injected. These large molecules are impermeable to the cell membrane and only diffuse to the plasma and interstitial spaces.
• Blood volume - Red blood cell volume can be measured with 51Cr-tag RBCs or by the formula: Calculated Blood Volume = Plasma Volume X 100/ [100-(0.87 X Hct %)], where 0.87 is the trapping factor.
• Plasma volume (PV)—This can be calculated using radioiodinated serum albumin (RISA) or Evans Blue dye, as they are specific to the plasma space.
• Intracellular fluid volume—This cannot be measured directly but can be calculated by subtracting ECFV from TBW, as the latter 2 variables are measurable.
• Interstitial fluid volume—This cannot be measured directly but is calculated by subtracting PV from ECFV, as the latter 2 variables are measurable.

Clinical Significance

Aside from the significance of the study of water balance on our physiologic understanding of the human body, the idea behind it is commonly seen in pathology and is presented clinically daily. Various conditions lead to an imbalance of water in the different compartments of the body; the specific imbalance can show in different ways and can be treated differently as well. The following presents 5 clinical scenarios where alterations in water balance can present. Each has an accompanying analysis of ECF volume, ECF osmolarity, ICF volume, and ICF osmolarity.

• Diarrhea—Diarrhea can be caused by a myriad of pathogens but is classically associated with isosmotic volume contraction.[11] As the lost fluid isosmotic, there is no net effect on intracellular fluid; the only change is a decrease in ECF volume, with osmolarity remaining unchanged.
• Diabetes Insipidus - In this condition, the body can either not produce ADH or the kidneys cannot respond to it, leading to a hyperosmotic volume contraction. In either case, there is a decrease in free water reabsorption from the distal tubules, leading to free water loss.[11] In this scenario, the osmolarity of the ECF increases, leading to an inflow of water from the ICF to the ECF, leading to ICF volume constriction. However, this flow of water across the membrane into the ECF compartment is not enough to compensate for the loss of free water; thus, there is constriction of the EFV as well. Lastly, as water is lost from the ICF compartment, the osmolarity of the ICF increases. The same changes would be expected in severe burns and excessive sweating, where there is excessive loss of free water.
• Conversely, excessive free water retention in SIADH results in the antithesis of what is seen in diabetes insipidus, leading to hypoosmotic volume expansion. In this condition, excess free water reabsorption in the distal tubule of the kidney leads to a decreased osmolarity of the ECF and an expansion of the ECFV.[12] Due to the decrease in ECF osmolarity, water flows into the ICF compartment, expanding the ICFV and decreasing the osmolarity of the intracellular fluid.
• Adrenal Insufficiency—In this case, there is low aldosterone, primarily leading to decreased tubular sodium absorption and hypoosmotic volume contraction.[14] In this case, sodium and water loss lead to decreased ECFV and decreased ECF osmolarity. Due to this decreased osmolarity, water shifts into the intracellular compartment, leading to ICFV expansion. Due to the decreased solute reabsorption, ICF osmolarity also decreases.
• Uremia - Often found in kidney failure. BUN can increase. However, an isolated state of increased urea would not cause a shift in the volume of either compartment nor would it lead to a change in osmolarity. This is because these changes are only accompanied by the addition or subtraction of free water or an osmotically active particle, meaning a particle that cannot freely cross the cell membrane.[13] As urea can freely cross the cell, it is considered non-osmotically active and, therefore, would not change osmolarity, thereby not leading to any shift of water balance.