Introduction

The body's fluids are primarily composed of water, which in turn contains many substances.[1] One such group of substances includes electrolytes such as sodium, potassium, magnesium, phosphate, chloride, etc. Another group includes metabolites such as oxygen, carbon dioxide, glucose, or urea. A third important group of substances is found in our body's water, including proteins, most of which are vital for our existence. Examples of proteins include coagulation factors, immunoglobulins, albumin, and various hormones.[1] 

The distribution of the body's fluids and the substances within them is critical for maintaining intracellular and extracellular functions pivotal to survival, so the body has developed tight mechanisms to control compartment composition. However, various clinical pathologies can alter the fluid composition and its constituents in the multiple compartments of the human body, which can have deleterious effects on our health and often require intensive interventions to monitor and maintain normal physiological conditions.[2] This topic primarily covers the physiologic composition of water in the human body, differentiates the body's various compartments and their associated volumes and compositions, describes how to measure these volumes, and delves into the clinical relevance of disturbances of normal physiological conditions.

Cellular Level

At the cellular level, the distribution of the body's fluid compartments is paramount to maintaining health, function, and survival. For the average 70 kg man, 60% of total body weight is water, amounting to 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: interstitial fluid volume (ISFV) and plasma volume (PV). One-third of the total body water is the ECFV, equivalent to 14 L. Of the extracellular fluid volume, 75% (10.5 L) is in the interstitial space, and 25% (3.5 L) is in the plasma.[3]

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

• The intracellular fluid comprises at least 10 distinct, minuscule cellular packages. For simplicity and to facilitate analysis of the intracellular space, the concept of a unified intracellular “compartment” has been introduced. These collections have important unifying similarities such as location, composition, and behavior, which provide practical utility in studying physiology.[4]
• Interstitial fluid is the fluid between and around bodily tissues. 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 single, continuous fluid collection. It differs from interstitial fluid by its higher protein content and its role in transport. Plasma is a component of blood and is often described as the “interstitial fluid of the blood,” as it bathes the suspended red and white blood cells.[6]

Mechanism

Several principles control the distribution of water between the various fluid compartments. To understand the different principles, it is essential to recognize that the ingestion and excretion of water and electrolytes are tightly regulated to maintain a 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 (Pc) and interstitial (Pi) fluids, as well as the oncotic pressures of the capillary (Op) and interstitial (Oi) fluids. 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 influence each other very closely, as the cell 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 intracellular fluid volume result from alterations in ECF osmolarity but do not respond to isosmotic changes in extracellular volume.[8] However, any water flow into or out of the cell membrane results in proportional changes in the ECFV.

If a disturbance increases ECF osmolarity, water flows out of the cell and into the extracellular space to balance the osmotic gradient; however, the total body osmolarity remains elevated, and the cell shrinks. If a disturbance were to decrease ECF osmolarity, water would move from the ECF into the ICF to attain osmotic equilibrium; however, 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 seem abstract, especially when discussing more theoretical compartments. Therefore, it is crucial to have a way to physically measure the volumes of the different compartments. 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 uniformly distributed within the compartment of interest.

Using this method, individual volumes can be measured directly, and the volumes of others can be determined by subtracting the volumes of related compartments. This information can then be quantified 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): Measured using radioactive-labeled water or antipyrine. The idea behind this is that water gets uniformly distributed among all the different compartments. So, if one can measure the radioactivity in the water, then one can 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 diffuse only into the plasma and interstitial spaces.
• Blood volume - Red blood cell volume can be measured with 51Cr-tagged 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, since both 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 studying water balance to our physiologic understanding of the human body, the concept behind it is commonly seen in pathology and presented clinically daily. Various conditions lead to an imbalance of water among the body's compartments; the specific imbalance can manifest in different ways and be treated differently as well. The following presents 5 clinical scenarios in which alterations in water balance may 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 is 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 either fails to produce ADH or the kidneys fail to respond to it, leading to 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, causing water to move from the ICF to the ECF and resulting in ICF volume contraction. However, this flow of water across the membrane into the ECF compartment is insufficient to compensate for the loss of free water; thus, there is also constriction of the EFV. Lastly, as water is lost from the ICF compartment, its osmolarity 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, excessive free water reabsorption in the distal tubule of the kidney leads to decreased ECF osmolarity and expansion of the ECFV.[12] Due to the decrease in ECF osmolarity, water flows into the ICF compartment, expanding the ICFV and decreasing intracellular fluid osmolarity.
• Adrenal insufficiency: In this case, aldosterone is low, primarily leading to decreased sodium reabsorption in the distal tubule 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 expansion of the ICFV. Due to the decreased solute reabsorption, ICF osmolarity also decreases.
• Uremia: Often found in kidney failure. BUN can increase. However, an isolated increase in 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.  

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Disclosure: Abraham Tobias declares no relevant financial relationships with ineligible companies.

Disclosure: Brian Ballard declares no relevant financial relationships with ineligible companies.

Disclosure: Shamim Mohiuddin declares no relevant financial relationships with ineligible companies.