Intracellular versus Extracellular Space: There’s a Third Space?

fluid management

What is the patient’s fluid balance? How much oral intake are they having? What rate are their nasogastric feeds running at? What about their intravascular fluid replacement? Do they have a large urine output? Have they been vomiting or having large amounts of diarrhoea? Are there insensible losses such as extreme diaphoresis? When assessing the fluid status of a patient, the amount of fluid in versus the amount of fluid out tends to be the main focus. However, understanding where fluid may be sitting within the body is of utmost importance for us to optimally manage our patient’s fluid status.

Intracellular versus Extracellular Space

Let’s all take a moment to review the differences between the intracellular and extracellular space, and importantly highlight that the extracellular space consists of both the intravascular space and the interstitial space.

The intracellular space: the space found within the cells that holds approximately 2/3 of the total body water. An optimal amount of fluid is required within this space to ensure that the cells do not become too dehydrated, or too swollen potentially leading to cellular rupture.

The intravascular space: the space found within the blood vessels. An optimal amount of fluid is required within this space to ensure adequate preload, cardiac output, blood pressure and perfusion.

The interstitial space: the non-functional space between the intravascular and intracellular space, also known as the third space.

Extracellular versus intracellular space

Oncotic versus Hydrostatic Pressure

To maintain equilibrium, fluid generally moves from the intravascular space to the intracellular space and vice versa. The movement of fluids occurs as a result of two very important pressures within our bodies.

Oncotic pressure: think of this as the “pulling” pressure within the intravascular space. The oncotic pressure keeps fluid in the intravascular space by either holding on to it or pulling it from the interstitial or intracellular spaces. The oncotic pressure is predominantly influenced by the large proteins, such as albumin, found within the intravascular space. It may also be referred to as the colloid osmotic pressure or the oncotic pull.

Hydrostatic pressure: think of this as the “pushing” pressure within the intravascular space. The hydrostatic pressure pushes fluid out of the intravascular space, into the interstitial or intracellular spaces. The hydrostatic pressure is predominantly influenced by any condition that will increase the amount of force the blood within the intravascular space exerts against the vessel walls.

oncotic pressure versus hydrostatic pressure

As the image above highlights, oncotic pressure remains the same whether it is on the arterial or venous side, as the large proteins within the blood remain the same on both sides. However, hydrostatic pressure is greater in the vessels on the arterial side compared to the venous side due to blood being forced into the arterial system from the heart during systole. Therefore, fluid will push out of the intravascular space on the arterial side. That fluid is pulled back into the intravascular space on the venous side due to the oncotic pressure being greater than the hydrostatic pressure.

What is Third Spacing?

Understanding the various spaces that can contain fluid within our body and the pressures that affect fluid movement within our body, brings us to some important points that explain the concept of third spacing:

  1. In order for fluid to move between the intravascular and intracellular spaces, it must travel through the interstitial space
  2. If the intravascular space has increased hydrostatic and/or decreased oncotic pressures, there will be more fluid pushed out of the arterial side and/or less fluid pulled back into the venous side, respectively
  3. These pressure imbalances can cause fluid to become trapped within the interstitial space, resulting in fluid accumulation colloquially known as third spacing

How Does Third Spacing Occur?

There are numerous pathophysiological occurrences within the body that can lead to third spacing, and it all comes down to conditions that increase the pushing strength and/or decrease the pulling strength related to fluids within the intravascular space.

  1. Low albumin levels
    • Albumin is a predominant protein within the intravascular space that increases colloidal oncotic pressure
    • Low albumin levels reduce the ability of the intravascular space to keep fluid within or pull fluid back from the interstitial space
  2. Fluid overload and/or congestion
    • As large volumes of fluids are administered into a relatively fixed intravascular space, there will be more pressure exerted by this fluid against the vessel wall
    • This increases hydrostatic pressure within the intravascular space resulting in fluid being pushed out more readily on the arterial side, and/or offsetting the oncotic pull on the venous side
    • The same principle applies with fluid congestion that often occurs in heart failure, with an increased amount of hydrostatic pressure building in the venous system causing third spacing into the lungs (pulmonary oedema), peripheries (peripheral oedema) and liver (ascites)
  3. Increased capillary permeability
    • While the vessels encompassing the intravascular space need to be permeable to allow movement of fluid, fluid will move out of the intravascular space more readily if capillary permeability is increased
    • The increase in capillary permeability is often seen in damage to the vessel wall as a result of burns or other forms of tissue trauma for example, or as part of an inflammatory process
  4. Decreased sodium levels
    • As water often follows sodium, hyponatremia may result in fluid not moving as readily back into the intravascular space

The Clinical Impact of Third Spacing

What is the practical relevance of fluid accumulation within the third space? Well, this is essentially fluid sitting in an area that cannot be utilised by the body for normal physiological processes. Remember those peripherally oedematous patients you have looked after? Or what about that patient with ascites? That’s right, these are examples of third spacing!

pitting oedema assessment

And what about those patients who appear hypovolemic with hypotension, tachycardia and feeling peripherally shut down? However, their fluid balance appears to be significantly positive? Remember, only fluid sitting in the intravascular space contributes to blood pressure. Therefore, a patient can definitely be hypovolemic despite appearing to be fluid overloaded; if this fluid is sitting in the third space!


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