Alberto J. Muniagurria

Edema is the increase in volume of the interstitial fluid, which is the extravascular portion of the extracellular compartment. The increase in the fluid content of the interstitial space may be several kilos before it becomes evident on physical examination, except the evolution and weight of the patient are monitored daily.

Its presence is detected by compressing the skin on a plane of resistant tissue, which leaves a mark or "sign of the fovea".

For better understanding, edema is classified as localized and generalized. Localized edema may appear on a limb, in an area of ​​the trunk, or in a cavity; in the latter case, hydrothorax is the accumulation of fluids in the pleural cavity, and ascites is the accumulation in the peritoneal cavity. Localized edema frequently occurs in traumatic symptoms, allergic reactions, burns, or venous or lymphatic obstructions.

The generalized edema responds to an alteration of numerous mechanisms in which the retention of sodium and water predominates especially. Marked, generalized edema is called anasarca, which can be accompanied by hydrothorax and ascites. It is found in heart failure, liver cirrhosis, nephrotic syndrome, malnutrition, or diseases of intestinal malabsorption.

Pathophysiology.

The entry or exit of liquids from the vessels to the interstitium is governed by Starling's law, which relates, on the one hand, the capillary hydrostatic pressure and the oncotic pressure of the interstitial proteins, and on the other hand, the tissue pressure of the interstitium and the oncotic pressure of intracapillary proteins, which, with the electrical charge of circulating ions in the blood, tend to retain fluid in the intravascular space.

Capillary hydrostatic pressure is determined by:

1) The flow within the capillary, its length and the resistance that exists to said flow, 2) the post-capillary resistance, and 3) the venous hydrostatic pressure. The hydrostatic pressure at the arteriolar level is greater than at the venous level, and that is why circulation occurs.

As for interstitial proteins, their concentration is very low, which is why their influence is very small. Therefore, the most important forces are the capillary hydrostatic pressure and the oncotic pressure of the intracapillary proteins together with the charged ions.

From the resultant of these forces there is usually a small movement of fluid from the intravascular space to the interstitial space. This is recovered by the lymphatic system, which returns the interstitial fluid to the intravascular space via the thoracic duct. In other words, the hydrostatic pressure is opposed to the oncotic pressure of the plasma proteins (mainly albumins) with a slight gradient towards the interstitium, which is reabsorbed by the lymphatic vessels.

Any variation at the level of hydrostatic, oncotic or lymphatic pressure, or the permeability of the vascular wall, will produce a movement of fluids into the extravascular space. If the process is extended producing a decrease in the effective arterial volume, or volume that is circulating in the arterial intravascular compartment, secondary variations will be generated that induce the retention of sodium and water by the kidney, which are not retained in the vessels, increasing the volume of the interstitial fluid and developing generalized edema. In this case, the third factor or volume factor or cardionatrin hormone does not act, probably due to the fact that the circulating effective arterial volume is decreased, unlike what happens in water and salt retention tables with normal or increased effective volume, where the third factor would be a defense element that would block the retention of sodium and water when the plasma volume increases. An example of this would be Primary Hyperaldosteronism. On the other hand, in dehydration or hemorrhage the circulating arterial volume is decreased, and therefore mechanisms are mobilized for the retention of water and sodium in order to return the volume to its normal values. In this case, the capillary hydrostatic pressure, the oncotic pressure, the capillary permeability and the lymphatic pressure are not altered, and consequently edema will not develop. In dehydration or hemorrhage, the circulating arterial volume is decreased, and therefore mechanisms are mobilized to retain water and sodium in order to return the volume to its normal values. In this case, the capillary hydrostatic pressure, the oncotic pressure, the capillary permeability and the lymphatic pressure are not altered, and consequently edema will not develop. in dehydration or hemorrhage, the circulating arterial volume is decreased, and therefore mechanisms are mobilized to retain water and sodium in order to return the volume to its normal values. In this case, the capillary hydrostatic pressure, the oncotic pressure, the capillary permeability and the lymphatic pressure are not altered, and consequently edema will not develop.

 The different primary factors that generate edema are:

1. Increased hydrostatic pressure: An obstruction in the natural drainage of the venous circulation will produce an increase in the capillary hydrostatic pressure, which will overcome the oncotic pressure of the proteins and cause a transudation of fluid into the interstitium. A localized edema may be due to venous obstruction in one or both limbs, or in the venous outlet of a cavity such as the pleural or abdominal cavity, producing hydrothorax or ascites, respectively. This passage of liquids will occur until the tissue pressure of the gap equals the capillary hydrostatic pressure, that is, until the existing pressure difference is corrected creating a new state of equilibrium. The lymphatic pathway is responsible for maintaining fluid flow by making it circulate, and therefore there is always a fluid leak from the intravascular to the interstitial space.

In the case of generalized edema, the increase in capillary hydrostatic pressure occurs due to the increase in central venous pressure in the right ventricle, whose ability to expel blood is decreased. Increased capillary hydrostatic pressure leads to fluid transfer to the interstitium, which decreases the arterial plasma volume in favor of the interstitial volume. This is seen in right heart failure or thrombosis or obstruction of a vein that drains into the heart, as well as constrictive pericarditis.

2. Reduction of oncotic pressure:  Any mechanism that alters the plasma concentration of albumin, causing it to decrease, will reduce the intravascular oncotic pressure of the capillary with fluid leaking into the interstitium. Albumin is the smallest protein with the highest concentration in plasma, and the one that most influences the control of oncotic pressure.

Malabsorption states and nephrotic syndrome are examples, one due to lack of incorporation, the other due to the real loss of proteins, hypoalbuminemia, which is accompanied by generalized edema.

3. Increased lymphatic hydrostatic pressure:  If there is no normal lymphatic drainage, there will be an accumulation of fluids and also of proteins, which will contribute to increasing the oncotic pressure of the interstitium.

This lack of lymphatic circulation may be due to the surgical removal of nodes (after breast cancer surgery), an tumoral or parasitic invasion of these structures, or increased hydrostatic pressure in heart failure.

4. Increased capillary permeability: When the capillary wall is injured, plasma is released into the interstitium. This will increase tissue oncotic pressure and contribute to increased fluid output. A burn, an allergic reaction or an inflammatory process will act by this mechanism generating localized edema.

Pathophysiology of heart failure, liver cirrhosis, and nephrotic syndrome. 

Whatever the primary mechanism of edema appearance, complex mechanisms are set in motion that tend to retain sodium and water and to generalize the problem. These mechanisms will be evaluated in different clinical syndromes.

1. Heart failure. It seems to be accepted that the first response of the organism to the decrease in cardiac output would be an increase in circulating blood volume, which is intended to compensate for this reduction in expenditure.
   
   Cardiac output or reduced minute volume produces, as an immediate response, a redistribution of circulation to preserve those organs or systems that the body considers of fundamental importance, such as the brain and heart, to the detriment of renal perfusion; that is, the renal blood flow decreases as demonstrated by the elimination of paraaminohipurate, with a preserved filtration rate, which is evidenced by the clearance of inulin; therefore the filtration fraction will be increased:
   
   Filtration fraction = GFR  (Glomerular Filtración Rate) / RBF (renal blood flow)
   
   This increase in the filtration fraction produces an increase in the osmotic pressure in the postglomerular capillaries, which generates an increase in proximal tubular reabsorption of sodium and water.
   
   If the glomerular filtration rate were reduced by a lesser degree of renal plasma flow, the retention of sodium and water would be even greater. That is, the lower the minute cardiac volume, the greater the retention of water and sodium. A second response would take place with the increase of the venous pressures at the level of the pulmonary and antegrade circulation, which increases the venous hydrostatic pressure and causes a transudation to the interstitium. The increase in hydrostatic pressure at the level of the thoracic duct contributes to increasing edema due to the fact that this habitual drainage mechanism is blocked.
   
   To further complicate these mechanisms, stimulation of the sympathetic system and the renin-angiotensin system occurs, with the consequent increase in renal vasoconstriction.
   
   According to the different authors, the renin-angiotensin system would be activated by the decrease in renal plasma flow, with stimulation of juxtaglomerular cells and therefore greater secretion of renin; The lower sodium concentration at the distal tubules level would also intervene, not to mention the aforementioned increase in sympathetic activity. The increase of renin (enzyme) would produce - by acting on the substrate angiotensinogen - angiotensin II, which contributes to renal vasoconstriction and therefore to the lower flow and the higher retention of sodium and water. In turn it stimulates the secretion of aldosterone by the glomerular layer of the adrenal cortex, which acts on the distal contoured tube retaining sodium. Without  doubt this is not the only mechanism of sodium and water retention, nor of the formation of edema, as can be seen in primary hyperaldosteronisms in which edema is not part of the picture. This would be explained by the fact that the effective plasma volume of the cardiac insufficiency is decreased due to the transudation of liquid and sodium into the interstitium, so that, no matter how much sodium and water are retained, these elements will not be retained in space. intravascular and therefore will not stimulate the secretion of the natriuretic hormone cardionatrin, or third factor, or volume factor. In other words, patients with heart failure do not increase natriuresis in response to an increase in sodium retention, as occurs in patients without heart failure. This would be explained by the fact that the effective plasma volume of the cardiac insufficiency is decreased due to the transudation of liquid and sodium into the interstitium, so that, no matter how much sodium and water are retained, these elements will not be retained in space. intravascular and therefore will not stimulate secretion of the natriuretic hormone cardionatrin, or third factor, or volume factor. In other words, patients with heart failure do not increase natriuresis in response to an increase in sodium retention, as occurs in patients without heart failure. This would be explained by the fact that the effective plasma volume of the cardiac insufficiency is decreased due to the transudation of liquid and sodium into the interstitium, so that, no matter how much sodium and water are retained, these elements will not be retained in space. intravascular and therefore will not stimulate secretion of the natriuretic hormone cardionatrin, or third factor, or volume factor. In other words, patients with heart failure do not increase natriuresis in response to an increase in sodium retention, as occurs in patients without heart failure. these elements will not be retained in the intravascular space and therefore will not stimulate the secretion of the natriuretic hormone cardionatrin, or third factor, or volume factor. In other words, patients with heart failure do not increase natriuresis in response to an increase in sodium retention, as occurs in patients without heart failure. these elements will not be retained in the intravascular space and therefore will not stimulate the secretion of the natriuretic hormone cardionatrin, or third factor, or volume factor. In other words, patients with heart failure do not increase natriuresis in response to an increase in sodium retention, as occurs in patients without heart failure.
   
   
2. Liver cirrhosis: The cirrhotic patient has a decreased effective arterial blood volume, and the same occurs with effective tissue perfusion. To this is added a marked decrease in albumin synthesis and probably its absorption due to the poor nutritional habits of the elite patient, which adds one more mechanism to those that come into play in heart failure. In this pathology, increased pressure at the portal vein level and obstruction of lymphatic drainage at the liver level are of great importance.
   
   
3. Nephrotic syndrome. The loss of proteins at the renal level, caused by the conditions that are accompanied by a nephrotic syndrome, explains the marked hypoalbuminemia characteristic of this pathology with the consequent filtration of fluids into the interstitium, which generates hypovolemia and sets in motion the mechanisms described in the heart failure. The same mechanism could explain the generalized edema of hypoalbuminemias due to malnutrition, protein-losing enteropathies, etc.

Semiology of edema

Localized edema: As described, they respond to regional venous, lymphatic obstruction, or both. The most frequent symptoms are those of lower limb edema due to venous thrombosis, or unilateral lymphedema in a lower limb due to neoplastic obstruction.

If the edema is located in a cavity, a puncture should be made and the characteristics of the liquid evaluated in the laboratory. Biochemical, microbiological and pathological studies are important to differentiate a transudate from an exudate. In transudates the liquid is clear, straw colored, with a density of less than 1,017 and a protein content of less than 3g / 100 ml; the cell count is low. In exudates, on the other hand, it is cloudy, it can be bloody or chylous, with a density greater than 1,017 and a protein content above 4g / 100 ml; the cell count is greater than 900 per ml.

Generalized edema:

1. Heart failure . The patient may have a history of dyspnea on exertion and lying as episodes of paroxysmal nocturnal dyspnea, nocturnal cough, fatigue, tiredness and evening swelling of the lower limbs,
   
   Compressing the skin with a finger will leave a mark or fovea, a sign that defines the box. The patient will present jugular distension, alternating pulse, cardiomegaly, ventricular and atrial gallop, bibasal rales, hepatomegaly with hepatojugular reflux, and sacral edema if in recumbency. The laboratory will only show elevation of uremia due to reduced renal perfusion due to decreased cardiac output.
   
   
2. Liver cirrhosis . The patient will have a history of alcoholism or liver disease, and jaundice, tiredness, anorexia, and weight loss. Physical examination shows jaundice, telangiectasias, palmar erythema, hepatomegaly, and sometimes splenomegaly, parotid swelling, gynecomastia, testicular atrophy, watch glass nails, and palmar Dypuytren retraction. Fluid accumulation begins in the abdomen, and generally begins in a period after a marked increase in gas.
   
   Analyzes reveal elevated serum bilirubin, abnormal liver function studies, low albumin levels, and moderate proteinuria.
   
   
3. The nephrotic patient. The questioning shows a history of systemic diseases with renal involvement, such as systemic lupus erythematosus and diabetes. The edema is morning, periorbital, soft and generalized. Urinalysis will show marked proteinuria of 3.5 g per day or more. In addition, hypoalbuminemia, hyperlipidemia, and hypercholesterolemia will be observed.

Depending on the location, we speak of edema localized to a certain region of the organism, or generalized; The important generalized edema is called anasarca, and may be accompanied by fluid accumulation in the serosae, which depending on its location will be called hydrothorax or pleural effusion, pericardial effusion, ascites,

Before the edema is clinically manifest, there is a less apparent degree, which is hidden edema, which can only be evidenced by weight gain. A daily variation of one kilo, in more or less, suggests the production or reabsorption of edema, so daily monitoring of weight in edematous patients is very important; if it is located, the circumference of the limb is measured.

The edema increases the volume of the tissues, so that upon inspection, changes can be detected, and the normal relief of the bones is erased. The skin appears thin and shiny, and in cases of chronic edema it appears hyperpigmented, with trophic changes and secondary fibrosis.

Palpation allows detecting edema if the skin is compressed with a finger against a bony plane, in the malleolar region, dorsum of foot or hand, pretibial region, sacrum, etc., maintaining pressure for several seconds; when removing the finger it will be seen that there is a depression, a sign of the fovea or Godet. When there is no bony plane, as in the flanks, a pinch of the skin and subcutaneous cellular tissue is made between the thumb and index finger, holding the pressure for several seconds, looking to see if the finger marks remain.

In the presence of edema, its characteristics should be determined. In the first place, its location, if it is observed in one or more regions, or is generalized. Edema widespread, especially at the beginning, has a predilection for certain regions. That of renal origin is evident in the lower eyelids, the cardiac in the lower limbs or in the sacrum if the patient is lying, the cirrhotic in the abdominal cavity (ascites), the venous in the affected limb or limbs, the inflammatory in the inflamed area or areas or in their vicinity.

The intensity of the edema can range from hidden edema to anasarca. The most common causes of significant generalized edema are heart failure, nephrotic syndrome, and liver cirrhosis.

The consistency of the edema must be determined; that of nephrotic syndrome and other hypoalbuminemias is soft. Those of chronic venous origin are harder and those of lymphatic origin are hard elastic, they are depressed little by pressure. Chronic edema, especially those of lymphatic or venous origin, if prolonged, lead to secondary trophic disorders of the skin and subcutaneous cellular tissue that harden the edema, frequently producing secondary microbial infections that accentuate these changes, reaching their degree maximum to elephantiasis.

The color of the skin varies according to its production mechanism. It can be reddish in the inflammatory ones; pale in kidney origin, bluish from cyanosis in stasis. In venous chronicles, there may be skin pigmentation and ulcerate.

The skin temperature is decreased, except in the inflammatory ones, where it increases due to vasodilation.

Inflammatory edema can spontaneously hurt, especially if it occurs in poorly compliant tissues; or on palpation. Angioneurotic edema is usually accompanied by itching, the others are painless.

The evolution of the edema must be determined; Angioneurotic edema is of sudden appearance and disappearance. The acute inflammatory is installed quickly and its duration is variable. That of nephrotic syndrome is accentuated in days, its duration depending on the evolution of the kidney injury. That of liver cirrhosi begins with ascites and then spreads to the lower limbs. In congestive heart failure and in the venous veins of the lower limbs, it begins with them, increases during the day and decreases or disappears at night.

In all patients with edema, the neck veins should be observed to determine if there is jugular engorgement typical of cardiac edema or compression of the superior vena cava or its tributaries. Hepatomegaly may exist in heart failure and liver disease. When examining the patient, the presence or absence of ascites, collateral abdominal (portal hypertension) or thoracic circulation (mediastinal syndrome), pleural effusion or signs of pulmonary congestion should be sought.

The weight should be measured daily, if it is located, the contour of the affected area is measured with a tape measure; 24-hour diuresis is requested in the laboratory to quantify urinary and plasma sodium and potassium, determine albumin in plasma, proteinuria, study urinary sediment and renal functionalism.

A differential diagnosis must be made between edema and myxedema; The latter is a hard, pale infiltration that does not leave Godet, caused by the deposition of mucopolysaccharides in the subcutaneous cellular tissue. It is observed in patients with significant hypothyroidism.

Problem management

1. First, it must be determined if the edema is localized or generalized. The most frequent causes of generalized edema have already been described »such as heart failure, nephrotic syndrome and liver cirrhosis. However, there may be difficulties in differentiating heart failure from cardiac tamponade. The Kussmaul sign (decrease in the amplitude of the arterial pulse during inspiration) as the wave and deep in the tracing of the jugular venous pulse orient in one direction or another. The differential diagnosis will be defined by means of a two-dimensional or M-mode echocardiogram or by performing an evacuation puncture of the pericardium.

2. Faced with generalized edema that does not obey cardiac, renal or hepatic causes, other less frequent pathologies should be considered, such as idiopathic cyclic edema, myxedema, trichinosis, hemiplegia, filariasis, lymphedema, etc.

3. Routine studies will include a complete blood count, uremia, urinalysis, thyroid function tests, albuminemia, angiotensin I dosing, cholesterol, liver function chest x-ray and an electrocardiogram.

4. If proteinuria, redness, and cylinds are found in the urine, parenchymal kidney disease should be sought.

5. A moderate to severe protenuria, 3.5 g / liter or more, suggests a nephrotic syndrome, even when not accompanied by hypoalbuminemia.

6. Hypoalbuminemia without proteinuria suggests malnutrition or protein-losing enteropathy if liver disease has been ruled out.

7. The diagnosis of idiopathic cyclic edema is based on the exclusion of the other causes in a young premenopausal patient, with large daily changes in weight (more than 700 g / day). She frequently accompanies unstable personalities. It can lead to a fluid retention of several kilos, which produces great anxiety in patients.