The ‘Third Space’–Fact or Fiction?

“While I was familiar with the concept of “third spacing”, I needed to clarify the implied “first”, and “second” spaces.”



Editor’s Note:

Back quite a while ago, I was really into publications, and the academic side of cardiac perfusion and education.  Part of what we do involves some major fluid shifts within the patient as a result of our prime constituents, pharmacological additives administered during the pump run, and the ability of the human body to physiologically compensate for dynamic fluid shifs and variances in Colloidal Osmotic Pressure (COP).

I was chatting with the surgeon while he was taking down the IMA, and mentioned that while I was familiar with the concept of “third spacing”, I needed to clarify the implied “first”, and “second” spaces.

It’s always cool (and almost glib) to nonchalantly dump out the phrase- “the pt is thrid spacing” as an explanation for where our volume might be hiding, or for obvious signs of tissue edema (puffy or swollen faces/hands and feet).

So anyway- here is some peer reviewed information regarding the vascular spaces we deal with 🙂


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The ‘third space’–fact or fiction?


For decades, the ‘third space’ was looked upon as an actively consuming compartment. Therefore, perioperative fluid regimens were traditionally based on a generous replacement of this assumed primary loss, in addition to deficits due to insensible perspiration and fasting. The practical consequence was an extremely positive fluid balance in order to maintain blood volume during major surgery. Whereas the insensible perspiration and the preoperative deficits are in fact often negligible, and the third space appears to be only a fictional construct, the excess fluid most likely accumulates interstitially. Such shifting is related to a destruction of the endothelial glycocalyx, a key structure of the vascular barrier, by traumatic inflammation and iatrogenic hypervolaemia. This explains why patients undergoing major surgical interventions benefit significantly from an infusion regimen which does not substitute but avoids ‘third-space shifting’. In summary, eradicating this notion from our minds could be a further key to achieving perioperative fluid optimisation.

The human body may be conceptually divided into two major fluid compartments: the intracellular compartment and the extracellular compartment. The intracellular compartment is the space within the organism’s cells; it is separated from the extracellular compartment by cell membrane.[1]

About two thirds of the human body’s water is held in its cells and the remainder is found in the extracellular compartment. The extracellular fluids may be divided into three types: interstitial fluid in the “interstitial compartment” (surrounding tissue cells and bathing them in a solution of nutrients and other chemicals), blood plasma in the “intravascular compartment” (the blood vessels), and small amounts of transcellular fluid such as ocular and cerebrospinal fluids in the “transcellular compartment”. The interstitial and intravascular compartments readily exchange water and solutes but the third extracellular compartment, the transcellular, is thought of as separate from the other two and not in dynamic equilibrium with them.[2]

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The Intracellular compartment

Intracellular fluid is contained by the cell’s plasma membrane, and is the matrix in which cellular organelles are suspended, and chemical reactions take place.[3] In humans, the intracellular compartment contains on average about 28 litres of fluid, and under ordinary circumstances remains in osmotic equilibrium. It contains moderate quantities of magnesium and sulphate ions.

Extracellular compartment

The interstitial, intravascular and transcellular compartments comprise the extracellular compartment.

Interstitial compartment

The interstitial compartment (also called “tissue space”) surrounds tissue cells. It is filled with interstitial fluid. Interstitial fluid provides the immediate microenvironment that allows for movement of ions, proteins and nutrients across the cell barrier. This fluid is not static, but is continually being refreshed and recollected by lymphatic channels. In the average male (70 kg) human body, the interstitial space has approximately 10.5 litres of fluid.

Intravascular compartment

The main intravascular fluid in mammals is blood, a complex fluid with elements of a suspension (blood cells), colloid (globulins) and solutes (glucose and ions). The average volume of plasma in the average (70 kg) male is approximately 3.5 liters. The volume of the intravascular compartment is regulated in part by hydrostatic pressure gradients, and by reabsorption by the kidneys.

Transcellular compartment (Third Space)

The third extracellular compartment, the transcellular, consists of those spaces in the body where fluid does not normally collect in larger amounts,[4][5] or where any significant fluid collection is physiologically nonfunctional.[6] Examples of transcellular spaces include the eye, the central nervous system, and the peritoneal and pleural cavities. A small amount of fluid does exist normally in such spaces.

Fluid shift

Fluid shifts occur when the body’s fluids move between the fluid compartments. Physiologically, this occurs by a combination of hydrostatic pressure gradients and osmotic pressure gradients. Water will move from one space into the next passively across a semi permeable membrane until the hydrostatic and osmotic pressure gradients balance each other. Many medical conditions can cause fluid shifts. When fluid moves out of the intravascular compartment (the blood vessels), blood pressure can drop to dangerously low levels, endangering critical organs such as the brain, heart and kidneys; when it shifts out of the cells (the intracellular compartment), cellular processes slow down or cease from intracellular dehydration; when excessive fluid accumulates in the an interstitial space, edema develops; and fluid shifts into the brain cells can cause increased cranial pressure. Fluid shifts may be compensated by fluid replacement or diuretics.

Third spacing

Third spacing is the unusual accumulation of fluid in a transcellular space. In medicine, the term is most commonly used with regard to burns, but also can refer to ascites and pleural effusions. With regard to severe burns, fluids may pool on the burn site (i.e. fluid lying outside of the interstitial tissue, exposed to evaporation) and cause depletion of the fluids. With pancreatitis or ileus, fluids may “leak out” into the peritoneal cavity, also causing depletion of the intracellular, interstitial or vascular compartments.

Patients who undergo long, difficult operations in large surgical fields can collect third-space fluids and become intravascularly depleted despite large volumes of intravenous fluid and blood replacement.

The actual volume of fluid in a patient’s third space is difficult to accurately quantify.

Third spacing conditions may include peritonitis, pyometritis, and pleural effusions.[7]

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