Edema is an abnormal accumulation of extracellular water resulting from malfunction of the physiologic mechanisms that regulate total body water, circulating intravascular volume, and the maintenance of cellular and extracellular electrolytes in the appropriate concentrations. Dysfunction in some or all of these systems can cause edema by one of two final pathways: (1) excessive filtration of fluid across blood capillaries, or (2) inadequate drainage of the interstitium by the lymphatic vessels. In this chapter we will provide an overview of the water regulatory mechanisms, then examine how the dysfunction of these mechanisms can lead to a state of edema using some common neonatal clinical scenarios to illustrate our current understanding.


edema, extracellular fluid, starling forces, plasma proteins, colloid osmotic pressure, capillary permeability, hydrostatic pressure, lymphatics


  • The Basics: Body Water Compartments

  • Starling Forces

  • The Role of Aquaporins in Regulating Fluid Balance

  • Factors That Combat the Development of Edema

  • Factors That Promote the Development of Edema

  • Unique Features of Water Homeostasis in the Neonatal Population

  • Special Circumstances in the Neonatal Population

  • Conclusion

Several systems act in concert to regulate total body water (TBW), allowing homeostasis of the circulating intravascular volume and maintenance of cellular and extracellular electrolytes in the appropriate concentrations. Edema, defined here as an abnormal accumulation of extracellular water (ECW), can result from malfunction of these fluid regulatory systems. This chapter provides an overview of the water regulatory mechanisms and then examines how the dysfunction of these mechanisms can lead to a state of edema. Lastly, the chapter examines some common clinical scenarios of the neonatal population that are associated with edema.

The Basics: Body Water Compartments

The volume and distribution of body water changes significantly during gestation and infancy. TBW is 78% of body weight at birth, but by 1 year of age, the percent of TBW declines to approximately 60%. There is a parallel decline in the ECW volume, which demonstrates a decrease from 45% of the TBW to 27% during the first postnatal year. As a result of the loss of ECW, the percentage of body weight that is intracellular water (ICW) increases during the first 3 months of age from 34% to 43%. This transient increase in ICW volume is followed by a decrease to around 35% at 1 year of age. At around 3 months of age, the ICW overtakes the ECW as the major contributor to TBW. This trend continues until, eventually, the ICW volume doubles that of the ECW.

Between 1 and 3 years of age, a slight increase is found in all three body water components, after which TBW and ECW decrease slightly until around puberty, at which point the adult values are reached. This decline in TBW and ECW that occurs between age 3 years and puberty is likely a result of the increase in both the quantity and size of cells in the major organ systems, especially the cells of the musculoskeletal system, the skin, and central nervous system (CNS). These three organ systems tend to retain more water in the intracellular compartment, leading to the decrease in both TBW and the proportion of ECW. TBW also is inversely proportional to the amount of body fat because of the low content of water in fat cells. During the first year of life, there is a very rapid increase in the amount of body fat. This is followed by a decrease during the preschool years and finally by a slight increase in amount of body fat during the prepubescent years. These changes in body fat composition correlate well with the above-mentioned changes in TBW. Overall, ICW appears to remain relatively constant, likely because the composition of the intracellular content remains constant.

Starling Forces

Water movement across an idealized capillary wall was described qualitatively by Starling in 1896 and can be defined by the following equation:

<SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='Jv=Kfc[(Pc−Pt)−σd(πp−πt)]’>Jv=Kfc[(PcPt)σd(πpπt)]Jv=Kfc[(Pc−Pt)−σd(πp−πt)]
J v = K fc [ ( P c − P t ) − σ d ( π p − π t ) ]
where J v is the volume flow of fluid across the capillary wall, K fc is the filtration coefficient of the capillary wall (volume flow/unit time per 100 g of tissue per unit pressure), P c is the capillary hydrostatic pressure, P t is the interstitial fluid or tissue hydrostatic pressure, σ d is the osmotic reflection coefficient of all plasma proteins, π p is the colloid osmotic pressure (COP) of the plasma, and π t is the COP of the tissue fluids. To best understand how the interplay of these forces affects overall fluid balance, it is best to analyze them individually.

Hydrostatic Forces

The hydrostatic pressure in the intravascular space (P c ) is the principle force driving water and electrolytes out of the capillary into the interstitial space. The filtration force of the capillary hydrostatic pressure is opposed by the tissue pressure surrounding the capillaries (P t ). Thus the net difference between capillary and tissue hydrostatic pressure (P c − P t ) is the driving force promoting filtration or absorption of fluid out of or into the capillary lumen.

Under physiologic conditions, the average capillary hydrostatic pressure is estimated to be about 17 mm Hg. An increase in small artery, arteriolar, or venous pressure will increase the capillary hydrostatic pressure favoring filtration. A reduction of these pressures will have the opposite effect. Whereas an increased arteriolar resistance or closure of arteries reduces the downstream capillary hydrostatic pressure, an increase in the venous resistance results in increased upstream capillary hydrostatic pressure. In general, changes in the venous resistance result in a greater effect on the capillary pressure than changes in arteriolar resistance.

In the nonedematous state, P t in loose tissues is close to zero or even negative (−1 to −4 mm Hg). Negative interstitial pressure often occurs under physiologic conditions when the lymphatic system is pumped from muscle contraction while there is minimal leakage of fluid from the intravascular space. Tissue pressure can change significantly if fluid moves into tissue space.

Osmotic Forces

The plasma COP (π p ) is the primary counterbalancing force to capillary hydrostatic pressure that promotes fluid retention in intravascular space. In his landmark publication, Starling demonstrated that this force is generated from the osmotic pressure associated with the plasma proteins. Total osmotic pressure of plasma approximates 6000 mm Hg, but most of this pressure is generated by the electrolytes, which are present in almost equal concentrations in both the intravascular and extravascular compartments of the ECW. In contrast, the plasma proteins are minimally present in the tissue surrounding the capillary. Therefore, the direct and indirect effect of the charged plasma proteins generates the difference in osmotic pressure, the plasma oncotic pressure. Normally, the plasma oncotic pressure averages 28 mm Hg.

Albumin is the primary plasma protein that is responsible for approximately 80% of the total COP. The other 20% is generated by globulins. It is the number of particles rather than the mass of a solute that determines its osmotic pressure. Thus, while albumin compromises only 50% of total plasma protein concentration, it has the greatest number of molecules present in the plasma and therefore makes the greatest contribution to the plasma oncotic pressure.

Another characteristic of albumin plays an important role through its effect on osmotic pressure. The albumin molecule has a net negative charge as the protein binds chloride anions. The charged albumin and its bound chloride attract cations (mainly Na + ). The excess cations within the intravascular space due to the albumin binding increase the osmotic pressure within the plasma significantly more than the albumin particles alone would generate. This is known as the Gibbs-Donnan effect. On average, the normal human COP is 28 mm Hg. Whereas 19 mm Hg is attributable to dissolved proteins, 9 mm Hg is generated by the imbalance of cations associated with the Gibbs-Donnan effect.

The interstitial fluid COP (π t ) is generated from smaller size proteins and the minimal amount of albumin that manages to leak out of the pores in the capillary walls. In healthy adults, the percentage of albumin that leaks into the interstitial space each hour is approximately 4% to 5%. This leakage of albumin is known as the transcapillary escape rate (TER), and it varies with capillary permeability, capillary recruitment, and hydrostatic pressure. The concentration of these proteins in the interstitial fluid is approximately 40% of the protein concentration in the plasma. Thus the average colloid osmotic interstitial pressure is about 8 mm Hg, favoring the movement of fluid into the intravascular compartment.

The Osmotic Reflection Coefficient

The reflection coefficient is the relative impediment to the passage of a substance through the capillary wall. The reflection coefficient of water across a capillary wall (fully permeable) is 0, and that of albumin (fully impermeable) is 1. Thus all solutes that can be filtered across a capillary wall will have a reflection coefficient between 0 and 1. The reflection coefficient of a substance depends both on the nature of the solute and the characteristics of the endothelial wall being crossed.

The reflection coefficient is a key component of the COP. True COP (π) is determined by the following equation:

<SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='π=σRT(Ci−Co)’>π=σRT(CiCo)π=σRT(Ci−Co)
π = σ RT ( C i − C o )
where σ is the reflection coefficient, R is the gas constant, T is the absolute temperature (in degrees Kelvin), C i is the albumin concentration inside the capillary, and C o is the albumin concentration outside the capillary.

The Filtration Coefficient

The filtration coefficient is an expression that quantifies the ability of a given fluid to cross the capillary wall. The filtration coefficient is proportional to the surface area of the capillaries, to the number of pores per centimeter squared, and to the radius of the pores raised to the fourth power. It is inversely proportional to the thickness of the capillary wall and to the viscosity of the fluid being filtered. Not only does K fc differ among the various organs, it may even increase or decrease within the same organ because of the closure or opening of more capillaries with similar conductance characteristics within a given organ.

Alterations in permeability of fluid or osmotic particles (either K fc or σ d ) may lead to edema formation without changes in either hydrostatic or osmotic pressure.

The Starling Hypothesis

The Starling hypothesis includes the factors previously described to relate direction movement across a capillary membrane. It is expressed mathematically as follows:

<SPAN role=presentation tabIndex=0 id=MathJax-Element-3-Frame class=MathJax style="POSITION: relative" data-mathml='Qf=k[(Pc+πi)−(Pi+πp)]’>Qf=k[(Pc+πi)(Pi+πp)]Qf=k[(Pc+πi)−(Pi+πp)]
Q f = k [ ( P c + π i ) − ( P i + π p ) ]

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Apr 4, 2019 | Posted by in NEPHROLOGY | Comments Off on Edema
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