Edema & Effusion

About 1/3 of total body water (TBW) is outside cells (extracellular space) and about 3/4 of this is between cells (interstitial fluid), with the remaining 1/4 inside the vasculature.

Terminology

• Edema = accumulation of fluid in tissues that is clinically noticeable. Remember, fluid stasis creates a favourable environment for bacterial growth!
• cerebral edema = can be diffuse or localized. As the brain swells, the gyri become distended and sulci become narrow. The brain has a fixed space in which to expand, so if the swelling progresses, it is pushed out of the cranium (herniation), often through the foramen magnum. 
• pulmonary edema = fluid accumulation in the lungs. The normally air-filled lungs become heavy, as the air is mixed with fluid and red blood cells from the capillaries. Fluid collects in the alveolar septa around the capillaries and in the alveolar spaces too. Fluid in the alveoli can allow for bacteria to grow leading to infection. 
• periorbital edema = fluid accumulation around the eyes. Renal disease often causes fluid accumulation in loose connective tissue like the eyelids. 
• subcutaneous edema = can be diffuse or localized. 
• dependent edema = influenced by gravity, meaning it accumulates in the legs when standing and the sacrum when lying down. 
• pitting edema = when you press over the subcutaneous edema (e.g. in lower leg) the interstitial fluid is displaced, leaving a depression i.e. "pit". 
• non-pitting edema = seen in thyroid disease (myxedema). Occurs due to deposition of hyaluronic acid, or lymphocytic infiltration and inflammation. 
• third-spacing = reversible expansion of interstitium. Protein-rich fluid can accumulate in tissues due to increased vascular (capillary) permeability i.e. capillary leakage. 
• Lymphedema = fluid accumulation in tissues due to impaired lymphatic drainage. Examples: post-mastectomy lymphedema (damage to axillary lymph nodes and lymphatic drainage leads to edema of arm), and lymphedema due to filariasis (parasitic obstruction of lymphatic vessels) called elephantiasis. 
• Effusion = accumulation of fluid in body cavities
• hydrothorax = fluid accumulation in the pleural cavity
• hydropericardium = fluid accumulation in the pericardial cavity
• hydroperitoneum (ascites) = fluid accumulation in the peritoneal cavity. The fluid accumulation can allow for bacteria to grow, leading to infection. 
• chylous effusion = occur due to lymphatic blockage, and when seen in the peritoneum, the fluid is often milky due to lipids absorbed from the gastrointestinal tract. 

• Inflammatory effusion/ edema = inflammatory mediators lead to increased vascular permeability allowing protein-rich fluid (exudate) to leave the capillaries and accumulate in the body cavities (exudative effusion) or tissues (exudative edema). The increased vascular permeability often allows for white blood cells to leave the capillaries with the fluid, creating a cloudy appearance to the exudate. 
• Non-inflammatory effusion/ edema = accumulation of protein-poor fluid (transudate); often translucent or straw coloured. 
• Hydrops fetalis = generalized accumulation of fluid in tissues and body cavities in a neonate. 

Pathophysiology

Edema occurs when there is an imbalance of pressure forces (called Staring pressures or Starling forces), or a failure of lymphatic drainage, or an increase in vascular permeability. There is a vascular hydrostatic pressure that tends to push fluid out of the capillaries and into the interstitium and a plasma colloid pressure that tends to push fluid back into the capillaries. These two pressures almost balance perfectly, however, there is a small net pressure pushing fluid into the interstitium. This little bit of interstitial fluid is drained away by the lymphatics.

Starling equation: Jv = Kf [ (Pc-Pi) - (π c- π i)], where Jv = the flow of fluid (mL/min), Kf = hydraulic conductance (mL/min/mmHg) i.e. the filtration coefficient; leaky capillaries have higher filtration coefficients. Pc = capillary hydrostatic pressure (mmHg), Pi = interstitial hydrostatic pressure (mmHg), π c = capillary oncotic pressure (mmHg), π i = interstitial oncotic pressure (mmHg). π = pi (3.14159..). 

• plasma colloid osmotic (aka oncotic) pressure - proteins (mainly albumin) in the plasma create an osmotic gradient for water, creating a tendency for fluid to enter the capillaries.
• edema and effusion can occur when plasma proteins are lost or when their production is reduced. 
• Examples: nephrotic syndrome (leaky glomerular capillaries allow albumin to enter the urine), liver disease (cirrhosis results in reduced production of albumin), protein malnutrition (kwashiorkor), etc. 
• edema and effusion can also occur when there is salt retention. Increased plasma sodium causes obligate water retention. 
• renin-angiotensin-aldosterone (RAA) system - this system is activated when there is reduced renal perfusion, heart failure, etc. Aldosterone causes sodium retention and the sodium attracts water, leading to edema. 
• vascular (capillary) hydrostatic pressure - the pressure exerted by the fluid in the capillaries on the walls. 
• edema and effusion can occur when hydrostatic fluid pressure in the capillaries increases, often due to impaired venous return. When venous return of blood is impaired, blood backs up into the capillaries and the hydrostatic fluid pressure increases. For example, in congestive heart failure, blood can't be pumped out and backs up into the veins, resulting in impaired venous drainage in tissues, and this results in increased hydrostatic pressure, and edema/ effusions.  
• lymphatic drainage - lymphatic vessels return any interstitial fluid and proteins to the vasculature. The lymphatic capillaries have one-way valves, which are supposed to prevent back-flow. The lymphatic capillaries carry the fluid into larger lymphatic channels and finally to the thoracic duct which empties this fluid into the veins. 
• damage to the lymphatic vessels, leads to impaired lymphatic drainage and the resulting fluid accumulation is called "lymphedema". For example, lymphatic vessels can be blocked due to parasites (e.g. filariasis) and later undergo fibrosis due to the inflammatory response to the parasite. They can also be damaged by radiation e.g. during breast cancer therapy. Sometimes, patients have poor lymphatic drainage because they have poor skeletal muscle compression of lymphatic that can not overcome gravity when standing. Remember, compression of lymphatics by surrounding skeletal muscles helps with lymph drainage. 
• Vascular permeability - when there inflammatory mediators increase vascular permeability, fluid, proteins, and cells are able to leave the capillaries and enter the tissues/ body cavities. For example, burns, sepsis, etc.  

Approach to Edema

First, assess if the edema is diffuse or localized.

• localized edema - occurs in one region of the body, e.g. one leg or arm (unilateral edema). It is often due to problems with venous drainage or lymphatic drainage. Conditions that cause localized edema include thrombophlebitis, chronic lymphangitis, parasitic infection of lymphatics, radiation of lymphatics. 
• superior vena cava (SVC) syndrome (image)- The SVC drains the face, neck and upper extremities, so when there is obstruction, edema is seen in these regions. 
• diffuse (generalized) edema - occurs all over the body, however, it is initially seen in loose connective tissues, e.g. eyelids (periorbital edema) and face. It is also more noticeable in the morning because the patient was lying down all night and fluid had time to collect in the eyelids (gravity helps it move down from face when standing). Look for the following causes of diffuse edema:
• decreased plasma proteins i.e. hypoalbuminemia (albumin < 25 g/L) which occurs in patients with liver disease (e.g. cirrhosis) because the liver can not make enough albumin, or patients with protein malnutrition, or in patients who are losing albumin in the urine (nephrotic syndrome)
• increased vascular hydrostatic pressure due to heart failure can cause diffuse edema. 
• salt retention due to renal hypoperfusion (RAA system) can cause diffuse edema. see above for explanation. Therefore, find out if urine output is reduced (oliguria) or absent (anuria). Also, drugs can affect renal perfusion by causing renal vasoconstriction (e.g. NSAIDs, cyclosporine) or can cause edema by increasing sodium reabsorption (steroid hormones). 

Specific Cases of Edema and Effusion

• Elephantiasis aka filariasis -- occurs due to infection with worm (Wuchereria bancrofti or Brugia malayi). This condition is most often seen in Asia, but can also be found in Africa, and South America. The filarial worm first infects mosquitos, which transmit it to humans. The worms leave the bloodstream and enter the lymphatics where they mature into adults and the adult form triggers an inflammatory response causing immune cells (macrophages, lymphocytes, eosinophils) to migrate to the area. The inflammatory response causes further edema and eventually fibrosis of the lymphatic vessel. The worms are often killed and calcified. The edema often is seen in the legs (but can occur elsewhere, e.g. scrotum), and the overlying skin becomes thickened and susceptible to infections (cellulitis). Treatment - Diethylcarbamazine (DEC) alone or combined therapy with diethylcarbamazine + albendazole or ivermectin + albendazole. DEC kills the adult worm and the baby form (microfilariae). WHO dosing recommendation. 
• pretibial myxedema (thyroid dermopathy) -- pretibial (shin) area is swollen and can become thickened and indurated. The edema is non-pitting because there is infiltration of inflammatory cells. The theory is that fibroblasts become stimulated and produce increased amounts of hyaluronic acid. There is also excessive mucin in the dermis. The reason for accumulation of infiltrate over the shins (pretibial area) is not clear, and it can be seen sometimes in other areas. It is not very common, and only seen in 1-4% of patients with Graves disease (hyperthyroidism), and usually after they begin treated. Treatments that have been used in refractory cases include: steroid injections, octreotide (remember, octreotide is an IGF-1 antagonist; theory is that IGF-1 over-expression on fibroblasts is part of the pathology).
• kwashiorkor - 
• hepatic cirrhosis - 
• congestive heart failure - 
• nephrotic syndrome -