Generalized edema

Generalized edemaIntroduction:

The history of edema, which has been observed since the beginnings of medicine, is linked to that of homeostasis, when knowledge of the body’s fluid sectors and their regulation emerge.Pathological increase of interstitial fluid, generalized edema reflects a disturbance of an essential mechanism of life: the system controlling body fluid volumes which ensures an exact balance between the amounts of salt and water absorbed and eliminated.

Essentially, sodium is confined to the extracellular space while the cells contain mostly potassium. Maintaining this distribution is largely achieved by the membrane enzyme Na-KATPase (adenosine triphosphatase), which is the homeostatic function. The role of sodium, a water-retaining tonomole, is crucial in the adjustment of extracellular volume. Thus, the central and truly motor device of the pathophysiology of generalized edema is that of the sodium balance.

The involvement of the kidney in the genesis of edema is linked to its role in maintaining the composition and volume of the fluid compartments within physiological limits, and in particular in adapting urinary excretion of sodium to food intakes. The lack of renal excretion of sodium, in view of the entries, causes the formation of generalized edema, whether the alteration is primitively renal or depends on extrarenal processes of which the kidneys are victims.Numerous mechanisms and their intrications make the understanding of the pathogenesis of edema, which are encountered in various pathological conditions, complex. Therapeutics aims to rectify the excess of the hydrosodic balance by modulating sodium inputs and outputs and then to maintain a constant balance to avoid the reconstitution of the edema, as long as the initial cause persists.

For several decades, the availability of diuretic medicines of increasingly better potency and pharmacological activity has transformed the life of patients with edema and reduced the most serious complications. However, some refractory edemas have not definitively disappeared, and their mechanisms are not all identified.

Current medical practice is concerned with the prevention of edema, in conditions involving exposure to it, or in early discovery of the cause of renal, cardiac, hepatic involvement … revealed by edema; the ideal being to have a true etiological treatment.

Description and definitions of edema:


Edema is a clinical symptom of abnormal fluid accumulation in subcutaneous tissues. Generalized edema is an increase in volume of the interstitial area of ​​the extracellular fluid, that is, the non-vascular part of the extracellular fluid compartment.

This increase in volume causes visible deformations.

Usually, patients with peripheral edema consult for a mainly evening swelling, sometimes with difficulty walking due to the accumulation of fluid in the legs or for an unsightly facial deformation.

The edema is asserted by the sign of the bucket: the finger leaves a lasting imprint on a deep, hard plane. It is more difficult to detect them in patients chronically bedridden, where they must be sought in the lumbar region or on the inner surface of the thighs. Generalized edema is indolent. The visible deformity is palpable and persists under a skin surface coating that is normal, non-inflammatory; in general, their topography is symmetrical.

Even before they are visible, the edema is characterized by an already significant increase in the liquid volume infiltrating the interstitial space. The subcutaneous deformations only become apparent from an increase of at least 5% of the extracellular volume. Weight gain is fundamental to the clinical measurement of edema. Changes in the weight curve indicate success or resistance to treatment.

The fluid infiltration can constitute a transudate and reach the serous membranes such as the pleura, the pericardium, the peritoneum, even the viscera, and alter the tissue functioning. Clinical signs are well known.

Edema may expose to high-grade accidents when it infiltrates cerebrom ening tissue, when the brain interstitial effraction overflows the reabsorption capacities of the glial cells. This encephalopathy, which is often rough at first, confusing in children, with a prognosis that is always formidable, is a medical emergency.

Pulmonary edema is not part of the generalized edema, although sometimes it appears as a major complication of extracellular expansion. When it is of hemodynamic origin, the excess volume and hydrostatic pressure of the small circulation creates a transfer of fluid through the point of weak resistance, the pulmonary capillary, towards the open medium.

The biological signs that translate the edema are very variable and especially disorienting. Albumin and total proteins, plasma hemoglobin can be lowered either as expected by dilution or due to the disease responsible for edema. In urine, concentrations of sodium and chloride ions are usually collapsed (except for therapeutic intervention) while that of potassium is high. The analysis of an effluent liquid shows that it is a transudate without inflammatory criterion. The usual imaging by ultrasound or standard radiography objectively serous effusions of the thorax and abdomen.

In clinical investigation, the evaluation of edema is first correlated with a first global measurement of the expansion of the extracellular volume by a dilution method (the inulin or isotopic space of the bromine). Plasma volume is secondarily subtracted using another tracer (iodinated albumin coupled to labeled red blood cells). This type of measure, used in scientific programs, is mainly validated for the repetition of the values ​​obtained in time for the same subject.

Edema represents an expansion of the interstitial volume but does not prejudge the state of the blood volume which may be normal, increased or decreased. This estimate, which is a function of each particular case, is imperative because it determines both the prognosis and the therapeutic decisions.

Hypervolemia is often accompanied by so-called volume-dependent arterial hypertension and carries the major risk of visceral edema: hypertensive encephalopathy, cometal crisis, etc. They are medical emergencies.

Hypovolemia is not always easy to establish but may pose a threat of collapse. A decrease in effective volume, which is responsible for effective tissue perfusion, may be dependent on disease or on the administration of diuretics. The effective circulatory volume can only be appreciated because it is not measurable. Its estimation is however decisive for the treatment.

Due to its complexity, accurate measurement of blood volume is reserved for clinical investigation.

The hydration of the intracellular area, measured indirectly by the natremia, may also be normal, increased or decreased.

It is dependent on the tonicity of the organism, and therefore on the water balance without electrolytes. Oedematous hydrosodic retention is usually isotonic, so the concentration of extracellular and plasma sodium remains normal. If the retention is hypotonic (positive balance of water without electrolytes), the tonicity and consequently the natremia are lowered. Isotonic retention calls for sodium restriction, hypotonic retention also requires a restriction of water. These notions emphasize that there is no “pass-through” treatment of generalized edema.


Localized edema is distinguished by its limited topographical character and by the usual contribution of a mechanical obstacle to their constitution. Asymmetric, the swelling seat in a single, restricted area, without the context of general sodium retention. The disturbance affects only one body segment, due to a local imbalance of the interstitial volume distribution.

Localized, noninflammatory edema with no surface skin lesions is due to a circumscribed alteration of the Starling forces responsible for fluid exchange in a limited area.

Starling Forces:

In the physiological state, fluid movements depend on the Starling forces in the capillary vessels. At the entrance to the capillary, the hydrostatic pressure tends to drive liquids from the intravascular to the interstitial space. This pressure is higher in the proximal part of the capillary and depends on the arterial pressure and the venous return. It decreases gradually along the ship.

Further downstream, the interstitial liquids can re-enter the vascular bed at the distal end of the capillary due to the low hydrostatic pressure. At this level, the concentration of intravascular proteins (oncotic pressure) increased. The interstitial fluid not drained by the venous capillaries is by the lymphatic circulation.


The physiopathology of localized edema is often evident: increased hydrostatic pressure, decreased oncotic pressure, primary alteration of capillary permeability or lymphatic obstruction.

The obstruction to venous drainage increases the capillary hydrostatic pressure upstream of the obstacle. This results in increased water transfer from the vascular area to the interstitium and the formation of venous edema. This condition, whether it is a consequence of phlebitis or post-lebiiti, whether it is compressive or related to chronic venous insufficiency, is very common. This scheme, however, only provides partial solutions to the treatment of these conditions and their trophic sequelae. Apart from a preventive attitude or drainage surgery, for lack of active venipotonic drugs, these edemas are rebellious. The obstruction of the lymphatic drainage also causes an accumulation of interstitial fluid. Edema may also result from an alteration of the capillary endothelium which allows abnormal extravasation of proteins to the interstitial area.

This phenomenon depends on the activation of local mediators.

Semiology of localized edema:

The diagnosis of localized edema is evident for inflammatory diseases such as phlebitis, erysipelas or gout attack taken by way of example, where red, hot and painful swelling goes without further description. For ecchymosis, burns or other caustic lesions, photosensitivity accidents, angioedema of the face, algodystrophies etc, circumstances and simple inspection are also sufficient for easy recognition.

Inflammatory infiltration is the result of local pharmacodynamic, chemotactic and cytokine mediators derived from invasive cells (lymphocytes, mast cells, polynuclear cells, macrophages) in response to physical, immunological or infectious aggression.

Local protein accumulation gives lymphedema and myxedema an elasticity and firmness that does not deform under pressure. There are, however, some special cases: ascites, partly secondary to complex localized forces at the portal level; cellular syndromes where a single obstructive lesion of the vein generates edema that is bilateral.

Some segmental edema, quite rare, it is true, is sometimes confusing, even if the lesion is found on an identifiable tissue. This is particularly the case for rhabdomyolysis (myocyte), fasciitis (aponeurosis), morphae (scleroderma), lymphangitis, elephantiasis and lymphocele (lymphatics).

Ultimately, localized edema is usually easily identified. Their specific causes are often discovered and treated as such: infectious, tumoral, immunoallergic, trophic, etc.

Physiopathology of generalized edema:


Balance of the sodium balance:

Generalized edema is a common medical condition, recognized for a long time. It is now well established that this is an increase in the hydrosodic content, the volume of the extracellular liquids being proportional to the sodium content.

For the past thirty years, most edematous situations have given rise to perfectly logical explanatory theories, giving full satisfaction both to the teacher, who is happy to describe a coherent sequence, and to the student, including without evil of evident cascades of events. These logical deductions, not generally resisting the progress of clinical investigations and experimental studies, are replaced by others, no less logical and indisputable, until our knowledge progresses a little. Quite often, these theories have suggested therapeutic behavior, and it is the failure or the unexpected result of it that has led to a new interpretation.

Our knowledge of renal function has increased considerably in recent decades and we can now describe how the kidney adapts to the sodium intake to maintain a physiologically adapted extracellular volume. In the healthy subject, the urinary excretion of sodium chloride corresponds to the intakes. When these increase, urinary excretion of sodium chloride becomes equivalent, but adaptation often takes several days. Excretion increases with a slight delay and temporarily, the extracellular fluid increases in volume before reaching a new equilibrium. There is a linear relationship between the volume of the extracellular fluid and the excretion of sodium chloride. The minimum value of the volume of the extracellular fluid for which the excretion of sodium chloride becomes zero is the excretion threshold. A considerable amount of sodium intake is required for the experimental increase in extracellular volume to correspond to a very slight edema.

The sodium, the main cation maintained in the extracellular compartment by the activity of the Na-K-ATPase membrane, is diluted in the water of this compartment. This dilution measured in plasma water is called natraemia. To maintain the equality between the extra- and intracellular tones (so that the cell volume does not vary), any increase in the amount of sodium must be accompanied by an increase in the amount of water (thus extracellular volume ).

This extracellular volume is subjected to various variations, either permanent or intermittent during the day and causing some of its decrease (sweating, water loss insensitive), the other its increase (dietary intakes). Ultimately, excreted urine represents the result of renal integration of these extracellular fluid alterations, glomerular filtration rate (DFG) and tubular reabsorption to ensure correct extracellular volume.

In other words, there is a balance of hydrosodic inputs and outputs at the kidney level, but the level of this balance depends on the level of sodium intake.

To be permanent, however, the achievement of this balance is not always accurate, but the assessment made over a few days remains quite nil. Sodium renal excretion depends on the state of expansion of the extracellular volume and more precisely on the volume of blood, rather than on the mass of the sodium intakes.

Generalized edema is characterized by a change in the slope of the linear excretion relationship of sodium chloride to the volume of the extracellular fluid and often by a displacement of the excretion threshold.

Renal Sodium Excretion:

It is outside of our subject to describe the renal mechanisms of soda transfer. It should be recalled that the DFG of the order of 180 L / d corresponds to the exit in the tubular urine of more than 25,000 mmol / d of sodium. The renal work is therefore to ensure considerable reabsorption. It is carried out through the tubular epithelium in which the basolateral position of Na-K-ATPase directs the transfer of sodium from light to interstitial space. Numerous neuroendocrine influences modulate this reabsorption, one of the essential effects of which is to tend to restore an extracellular volume perpetually diminished by glomerular filtration and frequently modified by the organism-environment relationships.


Nephrotic edema:

A clinical feature frequently associated with nephrotic syndrome, edema is often moderate and treatment combining sodium restriction and diuretic is sufficient. In a number of cases, however, the edema is desperate and seems to escape any treatment.

Classically, edema of the nephrotic syndrome is one of the easiest to explain to the medical student: proteinuria, a major component of nephrotic syndrome, leads to hypoproteinemia resulting in a decrease in plasma oncotic pressure resulting in a decrease of the plasma volume by extravasation of the plasma in the interstitial fluid.

The decrease in plasma volume stimulates the renal reabsorption of NaCl and water, which will increase the edema, the hydrosodic solution thus reabsorbed not being able to be maintained in the vessels. The result is a sort of vicious circle in which the initial disorder compromises the Starling equilibrium in the capillary circulation and the secondary disorder causes the hypovolemic stimulation of the hydrosodic reabsorption.

The reality is however very different and the elements of this scheme did not resist the experimental studies on the one hand, and especially the precise clinical studies on the other hand. In the 1980s, it appeared that the notion of hypovolemia (underfill theory) was not compatible with the data collected in patients, first in adults and then in children.The renal retention of sodium, perceived as caused by the extravasation of the serum, thus secondary to the edema, imposed itself as primary and at the origin of the edema.

The notion of edema by attempting to compensate for hypovolemia was based on four types of data:

– reduced plasma albumin;

– decreased plasma volume;

– stimulation of the renin-angiotensin II-aldosterone axis;

– significant sympathetic activity.

Experimentally, reduction of plasma albumin causes edema only when the transcapillary difference between serum and interstitial osmotic pressures is not maintained. However, when plasma proteins decrease, the concentration of interstitial proteins also decreases: the release of serum from the vessels dilutes the interstitial fluid, and especially the lymphatic flow increases. As a result, as the plasma concentration of albumin decreases, the absolute oncotic pressure of the plasma decreases, but not the difference in serum and interstitial oncotic pressures that remain in favor of maintaining the fluid in the vessels. It is only for very low values ​​of plasma albumin that this mechanism of protection against edema no longer works.

The edema of the nephrotic syndrome can be observed in patients without a significantly reduced concentration of albumin.

Measurement of plasma volume in adults and children usually gives a normal value. There are, however, a small number of patients with actual hypovolemia, but others have increased plasma volume. The measurement of blood pressure gives much more variable results (some patients are hypotensive, others hypertensive), the majority having normal values.

Stimulation of the renin-angiotensin-aldosterone system and sympathetic activity are considered as physiological markers of hypovolemia. Again, the data collected are divergent and many nephrotic patients do not show this hyperactivity of these neuroendocrine systems.

In contrast to this concept of hypovolemic edema, there are arguments in favor of a primitive hydrosodic retention by the kidney. The decrease of GFR in subjects with chronic renal insufficiency is an obvious cause. However, most patients with nephrotic edema have a correct GFR maintained.

Various works involve a primary alteration of the nephronic functioning without a precise localization being determined.An increase in Na-K-ATPase activity was demonstrated. It is due to an increase in the turnover of this enzyme (at least experimentally) which is not sensitive to ouabain. The sensitivity to aldosterone of Na-K-ATPase is variously reported, sometimes decreased, sometimes increased. From the therapeutic point of view, the same divergences are observed.Some using an antialdosterone diuretic can induce a negative soda balance (even though plasma aldosterone is normal). Others, using conversion enzyme inhibitors, decrease plasma aldosterone in their patients but without modifying natriuresis or limiting the increase in weight.

The role of the atrial natriuretic factor (FAN) is the subject of numerous investigations. The expansion of plasma volume in some patients has been shown to be accompanied by decreased response to FAN administration. It should be noted that our knowledge of the mechanisms of sodium reabsorption is constantly evolving and that the role of angiotensin II and FAN on the considerable proximal reabsorption is becoming more precise. It is possible to describe a balance between the actions of angiotensin II and their inhibition by FAN at the proximal cell.

In all, it seems that three groups of patients can be identified:

– those with discrete proteinuria (incipiens) and a near normal concentration of plasma proteins but with a clear sodium retention with high renal plasma flow, discretely elevated plasma aldosterone and normal adrenaline;

– those with severe proteinuria with hypoproteinemia and signs of net hypovolemia; the hydrosodic retention is accompanied by elevated plasma concentrations of renin, aldosterone and noradrenaline; the concentration of FAN is low and GFR is reduced;

– patients with severe proteinuria and hypoproteinemia but no evidence of hypovolemia: these occur with these edemas but with normal hormonal plasma levels and non-altered glomerular filtration.

Ultimately, edema of the nephrotic syndrome can only be explained by hypovolemia. In all cases, sodium retention has a primary kidney origin and often precedes hypoproteinemia.

Oedemas of acute renal failure:

Acute edema of glomerulonephritis is associated with arterial hypertension, hematuria, proteinuria and often acute edema of the lung. In this early stage of acute nephritic syndromes, the inflammatory and transient lesions of the glomeruli create a sharp and passive glomerulotubular imbalance. Reduction of GFR limits the flow of sodium to the tubules. This reduced amount of the filtrate is largely reabsorbed by the kidney tubes which remain intact because outside the lesion process. Natriuresis is therefore very reduced while the food intake maintained generates the edematous state. In accordance with the state of volumic expansion, renin and aldosterone concentrations are usually lowered. As for the role of the decrease in natriuretic factors, their deficit remains to be defined and there is no proof of the intervention of other extrarenal factors.

During acute oligoanuric kidney failure, the extreme reduction of GFR and urine flow makes explicit the oedematous appearance of sodium due to oral intake and perfusion. The sodium intake must be preventively restricted in all anuric or oligoanuric forms of acute renal failure (depletion excepted) as soon as the renal impairment is detected.

Oedemas of chronic renal insufficiency:

In chronic renal failure, during a prolonged phase of the disease, the kidneys retain an ability to balance the daily hydrosoded balance. Natriuresis and diuresis are conserved, there is no variation in weight, the edema only occurs at a phase of extreme reduction of GFR (less than or equal to 10 mL / min).

The tubular hyperfunctional capacity of the remaining intact nephrons is presented as the satisfactory explanation of this observation. The remarkable adaptation of this distal activity is only partially known. Attention has recently been drawn to the role of circulating natriuretic peptides. A characteristic of chronic kidney failure is however the slowness of the damping of a sudden load. Excess salt (alkaline waters, dietary gaps, medicines modifying renal hemodynamics) exposes more than elsewhere to accidents of small circulation overload before generalized edema.


The reduction of the effective circulatory volume (arterial blood volume between the left heart and the peripheral vascular resistances) is the most commonly used notion to explain the edema of congestive heart failure. It corresponds to the underfilling theory accepted for both low-flow cardiac insufficiency and high-rate heart failure. In the first case, the decrease in the effective circulatory volume is due to insufficient cardiac output, hence filling. In the second case, decreased peripheral vascular resistance (vasodilatation, arteriovenous shunts) prevents correct filling of sensitive arterial territory, despite increasing blood flow.

The famous debate between the theories of hypovolemia and hypervolaemia has become complicated in this field of a debate between the “precardia” (venous and pulmonary) and postcardiac (arterial) consequences. These various notions are not necessarily contradictory and can often be regarded as complementary.

The definition of heart failure, the inability of the heart to maintain a correct flow rate for normal filling pressure, results in considering only the deficit aspect of myocardial cell contractility. Now, this failure has causes, and these causes themselves have other consequences, essentially neuroendocrines.

The hydrosodic retention can not be attributed to the reduction of cardiac output alone, as it is also observed with high cardiac outputs. Similarly, in myocardial infarction in humans, or experimentally in animals, hydrosodic retention occurs even though cardiac output or venous pressure may not be altered.

Adrenergic blockade in human or experimental cardiac insufficiency produces marked natriuresis: administration of a b2 antagonist in the cardiac insufficient animal causes a decrease in sympathetic activity and an increase in urinary volume. The role of sympathetic hyperactivity appears clear in the reabsorption of sodium. Similarly, the renin-angiotensin system, aldosterone, FAN and endothelin (ET-1) are involved in this reabsorption. The increased activity of the renin-angiotensin-aldosterone system has been shown on several occasions. Baroreceptors of afferent arteriole are stimulated by a fall in renal perfusion. The resulting increase in renin secretion is mediated by local production of prostaglandins. Hyperactivity in the sympathetic, renin-angiotensin, and vascular endothelial systems (ET-1, nitric oxide [NO]) decreases GFR, thus promoting sodium retention.

The role of the FAN is more complex. Increased plasma concentrations of FAN, which are frequently found, may limit the elevation of plasma renin and aldosterone concentrations. Administration of exogenous FAN causes only a small increase in sodium excretion in patients with low-flow cardiac insufficiency. In total, the increase in FAN secretion in heart failure is insufficient to prevent hydrosodic retention; renal response to FAN is reduced; finally, its action is counterbalanced by increased secretions or formation of renin, angiotensin II, aldosterone and antidiuretic hormone (ADH).

Of hyperbaric origin, hypersecretion of ADH is usual in cardiac insufficiency; its consequences are manifold. The classic effect on the collecting tube promotes water retention. This increase in water reabsorption mainly results in hyponatremia, but it may facilitate edema, especially as an up-regulation of the aquaporins 2 of the water channels has been demonstrated. DHA increases peripheral vascular resistance and could lead to further deterioration of cardiac function.

Disturbances in capillary exchange have been studied. The hydrostatic pressure at the venous end increases and contributes to the onset of edema. This mechanism is counterbalanced by the arteriolar constriction that limits the formation of edema. The osmotic colloid pressure of the plasma varies little, whereas in the interstitial fluid it decreases; again, this mechanism limits the formation of edema. The equilibrium of Starling is altered in the direction of the constitution of the edema by different mechanisms: transmission to all the capillaries of the increase of the venous pressure, causing a modification of the filtration coefficient and an increase of the pressure hydrostatic, and also the development of a progressively inadequate lymphatic flow.

The glomerular capillary circulation is also modified. Renal perfusion decreases early in heart failure. The convergent actions of angiotensin II, FAN and the sympathetic system mean that the vasoconstrictor tone of afferent arteriole increases. DFG is therefore maintained, at least at the beginning of the course, despite hypoperfusion. One consequence is the increase in the filtered fraction, which increases the concentration of blood proteins in the peritubular circulation. This promotes an increase in the proximal reabsorption of sodium. When cardiac insufficiency progresses, renal hypoperfusion is more important, glomerular filtration becomes highly dependent on the formation of vasodilating prostaglandins of the afferent artery, limiting in the renal territory the general vasoconstriction caused by heart failure. The gradual decrease in GFR contributes to hydrosodic retention.

Finally, various factors, directly affecting the transport carried by the renal epithelium, have been either characterized or assumed.

Most of these factors are actually best known for slowing down or inhibiting sodium reabsorption. What one does not know is why they prove insufficient to prevent excessive sodium reabsorption. As we have seen, this same question also arises for the FAN.

In summary, the edema of heart failure is multifactorial: capillary disturbances, resulting in a decrease in the effective circulatory volume and shift to the extracellular fluid, reduction of the filtered sodium load by reduction of the renal perfusion, but especially a considerable hydrosodic reabsorption, considered to be of barosensitive origin, triggered by the decrease in the effective circulatory volume. At the beginning of evolution, these reabsorption mechanisms have a compensatory effect. These neurohormonal activations contribute to the maintenance of cardiac output. Gradually, they become deleterious to the heart itself, generating hypertrophy, ischemia, and also on the renal response that becomes inappropriate.

These complex but classical aspects are probably not definitive and the possibility that renal sodium retention in heart failure is a primary and not exclusively secondary phenomenon is envisaged.


A major retention of water and salt is characteristic of decompensated cirrhosis with ascites. The explanations given with regard to the responsible extrarenal disturbances have led to the confrontation of two successive theories of underfilling / overflow proposed now in complementary form.

According to the first hypothesis, underfilling of the arterial compartment triggers a sequence of events activating multiple vasoconstrictor neurohormonal systems. This results in stimulation of sodium renal reabsorption, failure to escape the aldosterone sodium retention effect and renal resistance to FAN. The factors of arterial and splanchnic vasodilation (in line with the clinical evidence of facial and palmar erythrosis, stellar angiomas, ascites, etc.) are still debated in cirrhotic patients. These include: NO, endogenous opioids, vasodilating prostanoids, glucagon, substance P, vasoactive intestinal peptide ….

Non-osmotic release of antidiuretic hormone occurs in the high frequency of hyponatremia in these patients.Aquaporins II are increased in experimental cirrhosis and this elevation is inhibited by V2 receptor antagonists. These new aspects offer interesting but still partial perspectives for the understanding and treatment of these edema. The latter are chronic, despairing and have high morbidity and mortality. The beneficial effects of spironolactone (also known to lower portal pressure) are similar to those observed in heart failure where aldosterone may be involved in the turnover of fibrosis.


Excessive intake of salt and / or intake of certain drugs may lead to edema. The possibility of iatrogenic edema should be considered when their cause is not clear. The increasing number of renal medicines multiplies these examples.

Excess of salt intake: the capacity for sodium excretion can be exceeded by excessive intake: abundant infusion of sodium chloride, sodium bicarbonate, medicines with high Na content often unknown, pathological salt hunger … The sodium intake become surplus when the excretion capacity is impaired: postoperative situation, elderly, decreased GFR …

Renal salt drug retention: Some drugs directly reduce sodium excretion. Diagnosis of these induced edema is difficult for subjects whose symptoms do not initially relate to renal, hepatic or cardiac involvement, which do not entail control of saline diet. In addition, self-medication may seem insignificant or denial.

Oestrogens: In their alkylated forms used in oral contraception, estrogens do not influence renal blood flow or GFR.Sodium retention is attributed to excessive synthesis of angiotensinogen, an increase in mineralocorticoids and possibly dysregulation of prolactin. These effects are less frequently observed with the prescription of mini-pills.

Vasodilator antihypertensive drugs: Generalized edema can be induced by vasodilators: minoxidil and to a lesser extent diazoxide. Volmia does not vary, arteriolar vasodilation causes a marked stimulation of the adrenergic, renin-angiotensin and antidiuretic hormone systems, resulting in sodium retention and oliguria. The joint prescription of diuretics may aggravate these edema by induced hypovolemia and often make them refractory to treatment.

Oedemas of non-steroidal anti-inflammatory drugs (NSAIDs): among the long-standing adverse effects of NSAIDs, prostaglandin synthetase inhibitors, edema has a frequency of 3 to 23% according to the studies. NSAIDs act by inhibiting the synthesis of prostanoids, local mediators of inflammation, but also regulating factors of soda excretion.

Along with nephrotic syndromes or acute renal failure induced by these drugs, there are cases of isolated edema.

These edemas, in humans, appear to be the consequence of changes in intrarenal rather than systemic hemodynamics. They are reversible upon discontinuation of treatment. With NSAIDs, the observed effects do not appear uniform and depend on the molecule used and especially the initial renal state. In the balanced subject, administration of NSAIDs has little or no effect on the kidney.

If renal perfusion is impaired, the reduction in GFR can be aggravated by the NSAID and edema may occur. The true therapeutic is preventive, especially in the elderly population, very exposed.

Oedemas of rebound at the discontinuation of diuretics: they are observed in people who habitually consume diuretics, either psychologically fragile, or women concerned about their aesthetics and alarmed by an apparent excess weight or swelling of the eyelids . Taking the diuretic causes extracellular depletion and tubular hyperactivity increasing the distal reabsorption of sodium. When the drug is discontinued, a positive sodium balance is established with a substantially natriuresis. The distal tubular hyperactivity is slow to correct, hence a phenomenon of rebound which can cause edema. They have sometimes been considered as “idiopathic” when they are the fact of dietary salt intake, become surplus in relation to the decreased outputs by the stoppage of the diuretic.

Conduct consists in interrupting diuretics by prescribing, for a few days, a reasoned restriction of caloric and sodium intake.

Anti-calcium medicines: they cause the most frequent medicinal edema. Dihydropyridines used to treat high blood pressure result in a high frequency of edema that can motivate discontinuation of treatment. This phenomenon is observed with all classes of analgesics. These symmetrical edemas, restricted to the legs and ankles, have only the appearance of generalized edema because the sodium balance is deemed to be in equilibrium.

The occurrence of flushes, headaches, following the taking of these drugs, suggests the installation of a vasodilatation.The treatment of edema of the lower limbs associated with the analgesics is not a priori a sodium restriction nor a diuretic prescription. Reduction of doses is not very effective, often these edema blur the symptomatology in the follow-up of the disease in question and, functionally inconvenient, require to be oriented towards another family of drugs.

Miscellaneous: Edema due to clomiphene citrate, dapsone, interleukin 2, ACE inhibitors in dialysis patients is known.Less convincing cause-and-effect relationships have been described for licorice, lithium, bromocryptin, recombinant growth hormone, anabolic steroids (doping), 1-blockers … Personal susceptibility may be a factor , as well as habits of excessive consumption of salt. Progress in pharmacovigilance, with better clarity of all these data, will enable prevention.


Orthostatic idiopathic cyclic edemas:

These periodic, capricious edemas occur in spurts of a few days or weeks in women of fertile age, intellectually evolved and socially active. This edematous edema tends to become widespread at the end of the day with a feeling of impasto of the size and tension of the breast. The variation in weight can be considerable and especially brutal, several kilograms after standing for a few hours. This criterion of orthostatism is fundamental in semiology. Sodium retention appears to be due to orthostatism as evidenced by the clinical sequence and improvement by strict decubitus. Access may occur during a premenstrual phase, a digestive episode, an affective event, but often without apparent cause.

Associated with various cardiovascular symptoms (orthostatic hypotension, arrhythmia …) and sometimes oliguria for several hours with no detectable metabolic consequences.

Chronic, gynecological (cycle disruption, galactorrhea), digestive (constipation), neuropsychic (headache, dysmorphophobia, irritation, depression, tetany, paresthesia …) symptoms are usually observed.

The etiological inquiry discovers no organic disease and always remains negative. This entity has only a clinical definition and no detectable cause. In the absence of preventive measures of access, patients who are disappointed and have an unstable psychology take refuge in a chronic and disorderly intake of diuretic and laxative medicines not devoid of serious potential: hypovolemic collapse, pronounced hypokalaemia, thrombosis accidents.

The main phenomenon appears to be a plasma transfer from the vascular to the interstitial. Oliguria, standing reduction of sodium and water excretion without electrolyte, appropriate hormonal response of catecholamines, renin-angiotensin system and hypovolemic-stimulated antidiuretic hormone are consistent with this hypothesis.

The abnormal variation in vascular permeability thus postulated is reversible. No organic lesions have been demonstrated although anomalies in estrogen regulation or prolactin …, or more recently renal dopamine production have been observed. This phenomenon of transfer is partly corroborated by kinetic studies of the albumin labeled according to the technique of

Landis. In fact, the mechanisms of these cyclic edemas remain to be explained.

Resting in clinostatism, decreasing sodium and carbohydrate intakes during edema flare, wearing compression stockings, and psychological management are the symptomatic measures to be proposed. Some drugs are sometimes effective: spironolactones, IEC, progesterone, bromocryptin, sympathomimetic agents, dextroamphetamines, which must be modulated according to the severity of the symptoms.

Premenstrual edema:

Idiopathic edema should be differentiated from the premenstrual syndrome (also cyclic) in which the appearance of sodium retention resolves itself to the onset of menstruation. A hyperestrogenic condition is incriminated, the treatment of which is generally sufficient.


Angioneurotic edema:

Inherited or acquired, they are associated with deficiency in C1-esterase inhibitor.

The hereditary form is autosomal dominant. Diagnosis is based on familial character, symmetrical localization of the face and extremities, absence of urticarial lesion, frequency of repetitive abdominal attacks (epithelial edema) and episodes of laryngeal edema. The inhibitory C1-esterase antigen is absent (type I). Other mutants have a non-functional protein (type II). The levels of C4 and C2, the natural substrates of C1, and the CH50 activity are lowered.The attenuated androgens (danazol) corrected the biochemical deficit and suppressed access.

An acquired form of inhibitory C1 deficiency associated with lymphoproliferative syndromes has the same clinical manifestations.

Oedemas of nutritional origin:

Prolonged protein deficiency may cause edema with hypoprotidemia. Often, heart failure due to vitamin B deficiency 1, malnutrition, hunger or alcoholism, depending on the field. Aggravating factors include: changes in cardiac output, opening of peripheral arteriovenous shunts, effective hypovolemia … to create tissue hypoperfusion and maintain edema. Uncontrolled renutrition increases the diet of ingested salt, it helps to maintain the edema.

In anorexia nervosa, in which malnutrition is not imposed by external events but results from a psychological behavior, edema is exceptional.

Clarkson Cyclical Shock Syndrome:

Very rare, Clarkson syndrome presents a lethal risk due to impressive shock attacks with major hypovolemia. In addition to the sudden plasma transfer from the capillary bed, there is monoclonal gammopathy. The relationship between chronic dysglobulinemia and the onset of access is only approximate (leukotrienes, interleukin 2-receptors, etc.). But treatment with theophylline and b 2-agonists seems to protect relapses.

Gleich’s syndrome:

This syndrome of generalized edema with hypereosinophilia includes stereotyped episodes of ten days of fever, with a drop in blood pressure and leucocytosis of 10 to 80% eosinophils. The degranulation of eosinophils is incriminated in capillary hyperpermeability.


Hypothyroidism, in which the myxedema is located in the pretibial zone, is sometimes associated with retro-orbital edema.

Among the incriminated factors, a disturbance of the lymphatic circulation seems to be the main cause.

Frequently observed oedemas are always unexplained: during alcohol withdrawal, in the immediate aftermath of hepatic grafts, when correcting diabetic ketoacidosis. Others, which are also frequent, are better known, such as posture edema, mechanical ventilation (prolonged resuscitation), or edema of transcontinental air travelers.


In children:

The edema is observed in three different conditions according to age.

– In the preterm infants, associated with hypoxia, hemodynamic instability induces wide and unpredictable variations in GFR. Other elements, multifactorial, such as tubular immaturity, excess salt intake during resuscitation …

– The anasarca by fetomaternal incompatibility is mainly found in its Rhesus-related form, during undeclared and unregistered pregnancies, Rhesus negative mothers not having benefited from the diagnosis and specialized treatment antenatal.

– In older children, in addition to the circumstances of kwashiorkor, the occurrence of edema leads to nephrotic syndrome, hypereosinophilia, exudative enteropathy, vitamin E deficiency.

During pregnancy:

The occurrence of edema is common during pregnancy.

Early, it suggests decompensation of an affection prior to conception; late, it announces pre-eclampsia. In fact, edema is no longer a criterion of preeclampsia, especially since its absence is an index of severity.

These complications are to be distinguished from isolated edema, more often observed close to the term. There is no arterial hypertension, no proteinuria, no urinary sediment abnormality, and all parameters are those of physiological pregnancy.

This finding of edema is not necessarily unexpected since it is believed that the normal expansion of the liquid volumes corresponds to the retention of 700 to 900 mmol of Na + . There is, however, no satisfactory explanation for this phenomenon, except to admit that in addition to a postural aspect, expansion is the accentuation of a physiological state (excessive oral load?).

The increase in circulatory circulatory flows and the ability to have normal or supraphysiological saline and water loads are the primary factors that favor overfill. On the other hand, peripheral vasodilation with lower systemic arterial pressure that occurs early in pregnancy, stimulation of the reninangiotensin system, abundance of progesterone, suppression of FAN, lower osmotic threshold of release of antidiuretic hormone and stimulation of thirst are consistent with the under-filling hypothesis.

Obstetric experience suggests that low salt diet is associated with increased gestational risk. Presumably overexpression, usually without danger, of a physiological state, these edemas are painful and tiring and justify a measured intervention (rest, correction of dietary differences, restraints).

Should we recall that in pregnant women, pulmonary edema (preeclampsia) is the only recognized indication of diuretics?

Therapeutic principles:

To treat edema, modern diuretics are simple prescription and proven efficacy.

Generally, the initial dose is effective and clinical monitoring (weight, pulse, blood pressure, respiratory status), framed by reasonable biological controls (hydroelectrolyte balance, renal state), allows for further treatment. But, usually, the cause of edema persists, chronic, and evolves for itself.

Treatment therefore has two aspects: to reduce the extracellular volume to its normal state, by reducing the excess balance in sodium, and to suppress as far as possible the conditions creating the positive balance, that is, to treat the etiology. We can not here enter into the details of the therapeutic measures proper to each etiology of the edema and its degree of gravity. It should be noted that current pharmacology offers mainly possibilities for edema of cardiac origin. Antiarrhythmic therapies, coronary oxygenation, vasodilators, ACE inhibitors, in brief all that improve myocardial performance, rectify preload and flow anomalies. They modify the consequences of downstream rapidly and durably, therefore edema.

In order to obtain extracellular depletion, it is necessary to restrict both the sodium (dietary, intravenous and medicinal) intakes and increase the hydrosodic outputs with natriuretic drugs.

The soda restriction is modulated. A strict diet of less than 80 mmol sodium / 24 h is hardly applicable beyond a few days. In our climates, a usual diet without addition of salt to foods still brings nearly 120 mmol of NaOH daily. It is more tolerable, but dietary adherence is a crucial point because sodium restriction is an obligatory condition to make negative the sodium balance under the effect of diuretics. Respect for this fundamental condition does not arise only in the patients’ homes. Even in hospitals, the exact assessment of entries can not always be accurate.

However, a number of supposedly resistant edemas are only the expression of the undue pursuit of sodium intakes.The urine sample of sodium and chlorine ion concentrations in the course of treatment can be very illuminating in this respect. Use in these cases of high doses of diuretics entails the risk of inducing sodium depletion which in turn stimulates the activation of compensatory mechanisms (catecholamines, renin angiotensin system, antidiuretic hormone, etc.) and maintains or even aggravates an alteration of the body ‘ hemodynamic and renal status of patients (reduction of GFR and increased reabsorption of sodium and tubular fluid). The evaluation of blood volume remains a crucial point before and during the whole prescription of diuretics.

Diuretics increase the excretion of water and electrolytes and these two activities are inseparable. The water restriction traditionally associated with salt limitation is only necessary when excess water without electrolyte causes hypotonicity of the extracellular medium (hyponatremia). This is a preventive measure when choosing a thiazide diuretic whose dipsogenic effect and impact at the distal tubular dilution site expose this type of accident. Progress is expected in the upcoming availability of V2 receptor inhibitors to improve the correction of plasma hypotonia, particularly rebellious, cirrhotic and certain cardiac. The principles of treatment of acute or chronic hyponatremia are then added to those of edema.

Should we recall that treating edema does not necessarily mean prescribing diuretics?

Rest in bed deactivates the sympathetic and renin-angiotensin systems …

Necessary for patients suffering from visceral edema, combined with the restraint of the lower limbs, it may simply suffice for medicinal edema, in a pregnant woman or with cyclic edema … Controlled studies attest that punctures are the treatment of ascites.

The debate remains open on the desirability of albumin infusions to treat nephrotic edema. Instrumental or interventional surgery is not only for compressive edema (urinary obstruction, valvular repair, derivation of portal hypertension …).

Finally, instrumental methods have been imposed in recent decades, rendering certain technical gestures (punctures of pericardium, pleura) or anecdotal (immersion) obsolete: dialysis techniques in renal insufficiency, hemofiltration techniques in acute or chronic complications heart failure, or in the preparation of liver transplants …

The long-term treatment of edema presupposes the maintenance of the sodium balance, once physiological equilibrium is obtained, when excess sodium chloride is reduced. Adequate dietary intake of salt and kidney excretion with diuretics and etiologic measures (tonicardiatics) are needed. The goal is to approach the physiological state, with a zero balance without excess or harmful depletion.

It is often a compromise, where edema must be limited and tolerable. This treatment, which is long-term, favors the natriuretic effect of medicines but presupposes dietary constraints, not always taxable in practice. Resistance to diuretics is the absence of bending or the reappearance of edema during treatment. The reality of this syndrome is considered once considered:

– lack of scalability of the initial disease;

– respect for dietary and medicinal adherence;

– the impact of any interactions (NSAIDs) or side effects related to prescriptions.

These situations usually lead to the prescription of increasing-dose furosemide or bumetanide, the bioavailability of which is considered to be more advantageous.

In the event of failure to obtain an adequate concentration of the diuretic at its active site, the venous route short-circuits the problems of intestinal absorption, the continuous perfusion avoids the phenomena of rebound. It then becomes logical to add a thiazide diuretic (or spironolactone) because the state of resistance reflects an increased sodium chloride reabsorption capacity at distal bypass tubes downstream of the loop diuretic-sensitive site. This combination is synergistic. The ultimate failure leads to hemofiltration / dialysis techniques.


The pathophysiology of generalized edema favors the role of sodium renal retention in all causes. It illuminates the therapeutic sequence which aims first of all to correct the expansion of the extracellular volume. Three interventions are involved: treatment of the etiology, dietary adherence and diuretics. Secondly, the second phase of maintenance is that of a permanent compromise because the cause usually persists and tends to increase edema again, while the balance of inputs and outputs obtained with diuretics must be maintained. It is during this period of maintenance that dietary compliance is paramount.