Edema Patophysiology

8/10/2019 Edema Patophysiology

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Edema patophysiology

Edema occurs when an excessive volume of fluid accumulates in the tissues, either withincells (cellular edema) or within the collagen-mucopolysaccharide matrix distributed in

the interstitial spaces (interstitial edema) . Our focus is on swelling of the extracellular

matrix or interstitial edema, which may occur as a result of aberrant changes in thepressures (hydrostatic and oncotic) acting across the microvascular walls, alterations in

the molecular structures that comprise the barrier to fluid and solute flux in the

endothelial wall that are manifest as changes in hydraulic conductivity and the osmoticreflection coefficient for plasma proteins, or alterations in the lymphatic outflow system,

as predicted by examination of the Starling euation.

Excessive accumulation of interstitial fluid is generally viewed as detrimental to tissuefunction because edema formation increases the diffusion distance for oxygen and other

nutrients, which may compromise cellular metabolism in the swollen tissue. !or the same

reason, edema formation also limits the diffusional removal of potentially toxic

byproducts of cellular metabolism. "hese are especially important problems in the lungs,where pulmonary edema can significantly impair gas exchange. #n some tissues, certain

anatomical structures limit the expansion of the tissue spaces in response to edemagenicstress. !or example, the $idneys are enveloped by a tough fibrous capsule, the brain is

surrounded by the cranial vault, and s$eletal muscles in the volar and anterior tibial

compartments are encased in tight fascial sheaths. %s a conseuence of the inability ofthese tissues to readily expand their interstitial volume, relatively small increments in

transcapillary fluid filtration induce large increases in interstitial fluid pressure. "his, in

turn, reduces the vascular transmural pressure gradient and physically compresses

capillaries, thereby reducing nutritive tissue perfusion &'*. #n the intestine, unrestrainedtranscapillary filtration leads to exudation of interstitial fluid into the gut lumen, a

phenomenon referred to as filtration-secretion or secretory filtration &+*. !iltration-secretion may compromise the absorptive function of the delicate intestinal mucosa andappears to occur as a result of the formation of large channels between mucosal cells in

the villous tips when interstitial fluid pressure increases by greater than mmg &+*.

%scites, or the pathologic accumulation of fluid in the peritoneal cavity, occurs incirrhosis and is caused by fluid weeping from congested hepatic sinusoids secondary to

elevated portal venous pressure &/*. %scites can predispose afflicted individuals to

peritoneal infections, hepatic hydrothorax, and abdominal wall hernias &/*.

ydrostatic edema refers to accumulation of excess interstitial fluid which results from

elevated capillary hydrostatic pressure while permeability edema results from disruption

of the physical structure of the pores in the microvascular membrane such that the barrieris less able to restrict the movement of macromolecules from the blood to interstitium.

0ymphedema represents a third form and may result from impaired lymph pump activity,

an increase in lymphatic permeability favoring protein flux from lumen to interstitialfluid, lymphatic obstruction (e.g., microfiliarisis), or surgical removal of lymph nodes, as

occurs in the treatment of breast cancer. 1estruction of extracellular matrix proteins, as

occurs in inflammation secondary to the formation of reactive oxygen and nitrogen

species and release of hydrolytic en2ymes from infiltrating leu$ocytes, resident immune


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cells, and cells comprising the tissue parenchyma, alters the compliance characteristics of

interstitial gel matrix such that interstitial fluid pressure fails to increase and oppose the

movement of fluid. #n addition, the tensional forces that are normally exerted byextracellular matrix proteins on the anchoring filaments (!igure /.') attached to

lymphatic endothelial cells to facilitate lymphatic filling are diminished as a result of

disrupted mechanical integrity &34*. 5eductions in circulating plasma proteins,especially albumin, produce edema by decreasing plasma colloid osmotic pressure, and

occurs in liver disease and severe malnutrition.

6o to7

3.'. "he 8argin of Safety %gainst Edema !ormation 9 Edema Safety !actors

:hile increases in capillary pressure, reductions in plasma oncotic pressure, and;ordisruption of endothelial barrier function are all accompanied by an increase in

transmicrovascular filtration, the accumulation of fluid is resisted by a number of edema

safety factors that wor$ in concert to limit edema formation. "his margin of safety against

edema formation was first recogni2ed in '4/ by


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raises interstitial colloid osmotic pressure (?t), thereby reducing the effective colloid

osmotic pressure gradient (B(?c @ ? (more...)

!igure 3.3. #nflammation results in the release of mediators that cause vasodilation,increase microvascular permeability, and induce leu$ocyte infiltration.

!igure 3.3

#nflammation results in the release of mediators that cause vasodilation, increase

microvascular permeability, and induce leu$ocyte infiltration. 5elaxation of vascular

smooth muscle cells in arterioles and precapillary sphincters results in a reduction(more...)

!igure 3.. 8yxedema is due to an accumulation of mucopolysaccharides secondary to

overproduction of fibroblasts.

!igure 3.

8yxedema is due to an accumulation of mucopolysaccharides secondary to

overproduction of fibroblasts. "his creates a suction force due to enhanced elastic recoil

of the extracellular matrix that creates a high negative interstitial fluid pressure (=t(more...)

#n addition to these basic compensatory mechanisms, the myogenic response to increasedwall tension in arterioles and venous bulging constitute other edema safety factors in

response to elevations in arterial or venous pressure in some tissues (!igure 3.') &++*.

8yogenic arteriolar vasoconstriction attenuates the rise in capillary pressure that mightotherwise occur in response to arterial or venous hypertension, and also acts to reduce the

microvascular surface area available for fluid exchange secondary to precapillary

sphincter closure &,''+,'/','*. :hen venous pressure is elevated, the volume of

blood within postcapillary venules, larger venules and veins increases and bulge into theextravascular compartment, thereby raising tissue pressure. #n effect, venous bulging

stiffens the extracellular matrix by increasing tensional forces on the reticular fibers and

fluid in this space &++*. !inally, changes in excluded volume with increased transcapillaryfluid filtration also comprise an important component of the margin of safety against

swelling of the extracellular matrix compartment &++,+*.

!rom the aforementioned discussion, it is obvious that tissues exhibiting restrictive

endothelial barrier properties, lowest interstitial compliance, and highest sensitivity of

lymph flow to changes in interstitial fluid pressure will exhibit the greatest margin of

safety against edema formation. Even in tissues where the endothelial barrier is lessrestrictive and lymphatic sensitivity is low, the margin of safety can still be uite

substantial if the interstitial matrix is stiff.

6o to7

3.. Aasogenic Edema

1isturbances in the vascular compartment are among the most common causes of

interstitial edema (vasogenic edema) and result from capillary hypertension or

hypoproteinemia. Capillary pressure (=c) is determined by arterial (=%) and venous (=A)

pressure and the ratio of pre- to postcapillary resistances (5%;5A) as shown by the


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euation &'4*7

#mage e3.'.Dpg3.'

sing gravimetric or venous occlusion methods to estimate =c provides values that range

between and '+ mmg in a number of mammalian tissues and represent a weightedaverage for all microvessels involved in fluid exchange within the organ &'3,'4*, while

direct measurements using micropuncture techniues in single capillaries yield values

that are considerably higher ('49/F mmg at the capillary midpoint) &+,/,3,,+,+F*when determined under conditions where net transcapillary filtration is either 2ero or

balanced by removal by lymph flow so that the tissue weight or volume remains constant

(isogravimetric;isovolumetric). "he discrepancy between values for capillary pressure

using these approaches largely reflects the fact that gravimetric and venous occlusionmethods yield estimates that represent pressure at the aggregate midpoint of vessels

involved in filtration of fluid from the blood to interstitium (i.e., capillaries and

postcapillary venules) under these conditions. Gased on model analysis and the fact that

direct micropuncture measurements of pressures within postcapillary venules rangebetween ' and mmg, it appears that the primary site of fluid filtration resides at or

very near primary site of vascular compliance &'3*.!rom Euation (3.'), it is apparent that capillary pressure rises when arterial or venous

pressure increases and;or the pre- to postcapillary resistance ratio falls. Since arterial and

venous pressure and the pre-to-postcapillary resistance ratio can be modified on amoment-to-moment basis in various physiologic (e.g., exercise) or pathologic conditions

(e.g., inflammation) or following administration of vasoactive pharmaceutical agents, it

might be expected that capillary pressure and thus transmicrovascular filtration rate can

rapidly increase in accord with these changes. owever, it has been suggested thatcapillary pressure may be tightly regulated in response to changes in arterial or venous

pressure, by appropriate adDustments in pre- or postcapillary resistance, as a means to

maintain a relatively constant interstitial fluid volume when any of these variables change&3,,''+,'/*. !or example, because vascular smooth muscle in arterial and arteriolar

walls contracts when exposed to elevated intravascular pressures, this myogenic response

increases precapillary resistance and protects capillaries from a concomitant rise in theirintravascular pressure. Conversely, when arterial pressure falls, myogenic tone is reduced

in arterioles, decreasing their resistance to flow and maintaining capillary pressure. "hese

observations suggest that capillary pressure may be regulated over the same range of

pressure changes over which flow is autoregulated in a given organ. #ndeed, from therelation7

#mage e3..Dpg3.

one would predict that blood flow (H) regulation would be perfectly coupled to the

regulation of capillary pressure, assuming that venous pressure and resistance remainconstant. owever, an extensive analysis of changes in the pre-to-postcapillary resistance

ratio and capillary pressure changes indicated that the effectiveness of flow and capillary

pressure regulation are not always closely correlated, an effect that may be due to passive

dimensional adDustments in capillaries and venules and rheological alterations in the


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blood flowing through these vessels as arterial pressure changes &,'*. #n addition to

the buffering effect of adDustments in the pre-to-postcapillary resistance ratio on capillary

pressure, the influence of changes in capillary pressure induced by alterations inperfusion pressure are minimi2ed by directionally opposite changes in the capillary

filtration coefficient secondary to recruitment or derecruitment of perfused capillaries

&'*.Similarly, changes in capillary pressure, and thus capillary filtration, are buffered when

venous pressure is elevated &,','3*. %t least two mechanisms account for this

regulation of capillary pressure (!igure 3.'). 8yogenic contraction of vascular smoothmuscle in the walls of arterioles is elicited by transmission of the venous pressure

increase to these upstream vessels &3,,3*. % venous-arteriolar reflex has also been

implicated in this response, wherein elevations in venous pressure activate antidromic

impulses that are transmitted to nerve endings impinging on upstream arterioles, whereneurotransmitter release elicits constriction &4,/3*. owever, more recent wor$ has

challenged the importance of this mechanism versus the myogenic response &F*. #t is

important to note that capillary pressure, and thus capillary filtration, is not as well

regulated in response to increases in venous pressure or resistance as when arterialpressure is altered &,'33*. owever, potential effects of increased venous pressure to

reduce the capillary filtration coefficient may buffer the response to altered capillarypressure on transmicrovascular fluid movement, as outlined above.

:hile the aforementioned discussion focused on the effect of acute changes in venouspressure on the regulation of capillary pressure and transmicrovascular fluid movement

and applies to most organs, the small intestinal vasculature may be uniue in its response

to chronic changes in venous pressure. Chronic intestinal venous hypertension induced by

calibrated stenosis of the portal vein is associated with the development of ahyperdynamic circulation characteri2ed by increased cardiac output, reduced intestinal

vascular resistance, and increased intestinal blood flow &'+,'4,','3*. "he latter changes

result in a larger increase in intestinal capillary pressure than occurs during acute venouspressure elevations of the same magnitude and are associated with increases in the

capillary filtration coefficient &'3*. %s a conseuence, the increase in transcapillary

filtration is much greater in chronic versus acute venous hypertension. "he mechanismsresponsible for the reduction in intestinal vascular resistance that account for the changes

in capillary pressure and capillary filtration coefficient that lead to enhanced capillary

filtration in chronic portal hypertension involve the formation of vasodilator substances

and other factors and are reviewed elsewhere &'+,'4,',+','',','3F*.

Capillary pressure is only modestly increased (I mmg) in chronic arterial hypertension

because the increase in arterial resistance that causes the rise in arterial blood pressurebuffers transmission of the pressure increase to the capillary level &'3*. Jevertheless, the

associated increase in transmicrovascular filtration rate largely accounts for the elevated

transcapillary escape rate of proteins noted in this disorder through convective couplingof fluid and protein flux. Elevated capillary pressure and filtration rate occur early in the

course of development of diabetes mellitus and is thought to be an important stimulus for

capillary basement membrane thic$ening, the ultrastructural hallmar$ of diabetic

microangiopathy &,'3/*. 8icrovascular rarefaction, or loss of capillaries, has been


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reported to accompany the development of arterial hypertension, diabetes mellitus, and

the metabolic syndrome &+,,/,,/,'3/*. "he attendant reductions in the surface area

available for exchange may partially offset the effect of capillary hypertension to increaseinterstitial fluid volume in these conditions.

Aery large increases in venous pressure may induce increments in capillary filtration farin excess of what would be predicted from the associated increase in capillary pressure.

"his is due to pressure-induced increases in microvascular permeability that are manifest

in the Starling euation by increases in hydraulic conductivity and reductions in theosmotic reflection coefficient. !or most organs, the permeability characteristics of the

microvascular barrier to the exchange of fluid and lipid-insoluble solutes can be

explained by the existence of large numbers of small pores with radii of angstroms or

less and a smaller number of large pores with radii in excess of angstroms, with somemodels incorporating a third set of very small pores (K ' angstroms in radius) to account

for the diffusional flux of water. (Organs such as the liver, which have discontinuous

capillaries characteri2ed by large gaps between endothelial cells and reflection

coefficients approaching .', do not fit these models). 0arge increases in venous pressureare thought to enlarge these pores in microvascular wall, which is referred to as the

stretched pore phenomenon &'44,'+,/+*. #ndividual organs demonstrate a differentialsensitivity to the effect of elevated venous pressure with regard to induction of the stretch

pore phenomenon. !or example, no increase in permeability occurs in microvessels of the

feet during uiet standing, even though capillary pressure in the feet increases by morethan mmg relative to values measured when supine, owing to the large hydrostatic

column in arteries and veins. owever, pulmonary capillaries may demonstrate a

stretched pore phenomenon during conditions such as left ventricular failure, an effect

that exacerbates pulmonary edema formation in this condition &'44*.

%s noted above, myogenic constriction of arterioles in response to elevations in arterial or

venous pressure constitutes an important safety factor against edema formation inhydrostatic edema by limiting the increase in capillary pressure and by reducing the

number of perfused capillaries, and thus the available surface area for fluid filtration, that

might otherwise occur in response to arterial or venous hypertension or increased venousresistance (!igure 3.'). owever, it is important to note even modest increments in

capillary pressure, which might appear to be small and inconseuential, can result in

substantial increases in fluid filtration rates across the microvasculature. "his is because

normal net filtration pressure is uite small, averaging .' mmg for a prototypicalbody capillary. "hus, increasing capillary pressure by Dust mmg, as noted above in

arterial hypertension, results in an initial '3-fold increase in fluid movement from the

blood into the interstitium. Capillary hypertension results in the formation of a protein-poor ultrafiltrate that upon entry into the interstitial space raises interstitial fluid volume.

Owing to the compliance characteristics of the interstitium, small increments in

interstitial volume produce very large increases in tissue pressure, which effectivelyreduces the transcapillary hydrostatic pressure gradient, thereby limiting further

accumulation of fluid (!igure 3.'). "his effect is exacerbated in response to elevations in

venous outflow pressure through the phenomenon of venous bulging. "hat is, the volume

in veins increases immediately on elevation of venous pressure, which produces a


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coincident increase in interstitial pressure caused by expansion of engorged venules and

veins into the interstitial spaces (!igure 3.'). #n essence, venous engorgement shifts the

interstitial compliance curve to the left, so that a smaller change in interstitial volumeproduces a larger increase in interstitial pressure. #ncreased interstitial fluid pressure

increases lymph flow by three mechanisms. !irst, increased tissue pressure provides the

driving pressure for flow into initial lymphatics. Second, increased pressure in theinterstitial compartment creates radial tension on the anchoring filaments connecting the

extracellular matrix to lymphatic endothelial cells, locally increasing initial lymphatic

diameter and opening gaps between interdigitating and overlapping Dunctions betweenadDacent lymphatic endothelial cells (!igure /.'). "hese tensional forces create a small,

transient suction pressure for movement of interstitial fluid through enlarged gaps

between adDacent endothelial cells, which act as a second, one-way valve system to

ensure unidirectional flow from the interstitium into lymphatics. "hird, as fluid movesinto initial lymphatics, it increases volume in upstream lymphangions, promoting their

contractile activity and lymph flow. "he presence of valves between adDacent

lymphangions assures one-way flow.

%s noted above, capillary hypertension results in the movement of protein-poor fluid into

the interstitial spaces, reducing the concentration of tissue proteins and decreasing tissuecolloid osmotic pressure (!igure 3.'). "his increases the effectiveness of the

transcapillary oncotic pressure gradient (?c @ ?t) in opposing the hydrostatic gradient (=c

@ =t) favoring filtration. Gecause solute is excluded from a large portion of gel water inthe extracellular matrix, the rapidity of the decrease in tissue protein concentration that

occurs in response to increased interstitial fluid volume is enhanced, thereby augmenting

the effectiveness of protein washdown as an edema safety factor. #t is important to note

that the effectiveness of decreases in tissue osmotic pressure as an edema safety factor isreduced in severe capillary hypertension, owing to the stretched-pore phenomenon

discussed above, which increases convective-coupled protein transport into the tissue

spaces.

6o to7

3./. ypoproteinemia

8ar$ed reductions in the circulating levels of proteins, especially albumin, is another

cause of edema that relates to intravascular factors (!igure 3.). ypoproteinemia may

result from rapid loss of proteins across a compromised glomerular barrier in diseased$idneys, impaired hepatic synthesis of plasma proteins in liver disease, severe

malnutrition or protein-losing enteropathy (which limits the availability of substrate for

protein synthesis), or from infusion of intravenous fluids lac$ing macromolecules. "heensuing reduction in the colloid osmotic pressure gradient (?c @ ?t), which favors

reabsorption in the non-steady state and opposes the hydrostatic pressure gradient that

favors filtration, induced by hypoproteinemia can result in a large transcapillary flux ofprotein-poor fluid into the interstitial spaces (!igure 3.). 0i$e capillary hypertension,

this effect is opposed by elevations in tissue hydrostatic pressure, which increases lymph

flow, both of which serve to limit the accumulation of tissue fluid (!igure 3.). Enhanced

capillary filtration also acts to dilute the concentration of proteins in the extracellular


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spaces, an effect that is magnified by increasing the accessible volume in the extracellular

matrix gel (!igures .' and 3.). "he ensuing reduction in interstitial colloid osmotic

pressure acts to reduce net filtration pressure, thereby minimi2ing edema formation.nli$e the response to vascular hypertension, there is no stimulus for myogenic arteriolar

vasoconstriction and venous bulging does not occur in hypoproteinemia, which reduces

the margin of safety for edema formation in response to this edemagenic stress. %s aconseuence, tissues are less able to compensate for reductions in plasma colloid osmotic

pressure that are euivalent to a given increase in capillary hydrostatic pressure.

6o to7

3.3. =ermeability Edema and #nflammation

1isruption of the microvascular barrier is a pathologic seuela in a large number ofdisease states, commonly accompanies trauma, and can be induced by a wide variety of

endogenously produced mediators and pharmacologic agents. #n the Starling euation

(Euation ('.3)), this increase in permeability is manifest as a reduction in the osmotic

reflection coefficient and;or an increase in hydraulic conductivity (!igure 3./). 5apidreductions in the reflection coefficient decrease the effectiveness of the colloid osmotic

pressure gradient in opposing filtration. "he reduction in the restrictive properties of theendothelial barrier allows movement of a protein-rich filtrate into the tissue spaces, which

increases interstitial colloid osmotic pressure (!igure 3./). "he resultant reduction in the

colloid osmotic pressure gradient increases net filtration pressure, an effect that isexacerbated by the fact that many if not most of the mediators that increase microvascular

permeability also act as vasodilators and reduce arteriolar resistance (!igure 3.3). %s a

conseuence, capillary pressure is elevated, which further increases net filtration

pressure. #n addition, vasodilatation tends to recruit capillaries, thereby increasingmicrovascular surface area available for fluid and protein flux into the tissues. "he latter

change contributes to a further increase in the capillary filtration coefficient (which is

eual to the hydraulic conductivity times surface area, 0pS), thereby magnifying theeffect of increased net filtration pressure to promote volume flux. "he mar$ed

enhancement in transcapillary fluid filtration results in increased convective transport of

protein through the enlarged pores in the microvascular barrier (!igure 3./). nder suchconditions, the effect of increases in interstitial fluid pressure and lymph flow to provide

a margin of safety against edema formation are rapidly overwhelmed and mar$ed

swelling of the interstitial spaces ensues.

=ermeability edema is exacerbated in inflammatory states that are characteri2ed by

leu$ocyte infiltration into the tissues (!igure 3.3). #nflammation is a characteristic

response to tissue inDury and involves the release of a large number of mediators that notonly increase microvessel permeability and cause vasodilatation, but also act to attract

leu$ocytes to the damaged tissue (!igure 3.3). "hese phagocytic cells release a variety of

hydrolytic en2ymes as well as reactive oxygen and nitrogen species that degradeextracellular matrix components and the anchoring filaments that attach to lymphatic

endothelial cells (!igures /.' and 3.3). "his reduces the radial tension on the valve-li$e

overlapping and interdigitating cell membranes at the interendothelial Dunctions in initial

lymphatics, which may compromise lymphatic filling. 0eu$ocyte-mediated disruption of


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the extracellular matrix components also increases interstitial compliance, which allows a

larger volume of extracellular fluid to be accommodated within the matrix with little

increase in interstitial fluid pressure, thereby attenuating the effectiveness of this edemasafety factor. "his effect is exacerbated by disruption of the connections fibroblasts form

with collagen fibers in the interstitial spaces, which normally help compact the

extracellular matrix by imposing tensional forces on these fibrillar components andrestrain the gel matrix from ta$ing up fluid and swelling (!igure ./). Extracellular matrix

disruption thus produces a more compliant interstitium that limits the increase in

interstitial fluid pressure for a given change in interstitial volume. Excluded volumes arealso reduced by matrix degradation, an effect that increases effective interstitial colloid

osmotic pressure. Extravasated proteins move more readily through the disrupted matrix,

facilitating blood-to-lymph transport of these macromolecules.

6o to7

3.. Jeurogenic #nflammation

Jeurogenic inflammation is characteri2ed by leu$oseuestration, edema formation, andextravasation of plasma proteins following stimulation of sensory neurons. Sensory fibers

release calcitonin gene-related peptide, substance =, and neuro$inin % when stimulated."hese proinflammatory molecules may act directly on the microvasculature to produce

inflammation, but also appear to activate tissue mast cells, which augment the

inflammatory response by release of their own complement of mediators.

6o to7

3.F. 8yxedema

8yxedema is caused by suction of plasma filtrate into the tissue spaces that occurs as a

result of overproduction of interstitial collagen and mucopolysaccharides by fibroblasts.

#ncreasing the density of these extracellular matrix components augments the elasticrecoil of the interstitial gel matrix and thereby producing a highly negative interstitial

fluid pressure (!igure 3.). %s a conseuence, lymph flow is reduced. #ncreased matrix

density also increases the excluded volume, which acts to increase the effectiveinterstitial colloid osmotic pressure. #n effect, these changes create a suction force that

accelerates fluid filtration and the development of edema. "he most freuent

manifestation of myxedema occurs in cases of hypothyroidism secondary to increased

deposition of tissue matrix &'34*.

6o to7

3.. 0ymphedema

Gecause lymphatic drainage represents the maDor route for removal of interstitial fluid

(and macromolecules) formed by capillary filtration, dysfunction of lymphatic vesselscauses the development of edema and can exacerbate edema induced by other causes

(!igure 3.F). 0ymphedema occurs with physical obstruction of the lymphatic vessel

lumen (either by extramural forces exerted by tumors or intraluminal obstruction by

metastasi2ing tumor cells), destruction or regression of existing lymphatics,


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incompetence of the valves between lymphangions, paralysis of lymphatic muscle,

reduced tissue motion, diminished arterial pulsations or venomotion, or by elevated

venous pressure at the drainage points where lymphatics empty into the systemic bloodcirculation (!igure 3.F). :hatever the cause of lymphatic dysfunction, edema formation

does not occur until lymph flow is reduced by L, all other factors being eual.

!igure 3.F. 0ymphedema arises in response to a variety of conditions that result in

reduced lymph flow.

!igure 3.F

0ymphedema arises in response to a variety of conditions that result in reduced lymph

flow. :hen lymphatic outflow (>0) is completely occluded, interstitial fluid volume

initially increases because capillary filtration (>A) occurs until the interstitial (more...)#n the case of complete obstruction, lymph flow draining a tissue region falls to 2ero.

"ranscapillary filtration into this tissue region continues until interstitial pressure rises to

eual net filtration pressure. %s transcapillary volume flux decreases, the convective

transport of protein from the vascular to interstitial compartments decreases. Sinceextravasated protein is not removed by the obstructed lymphatic, diffusional flux of

protein continues until the concentration gradient is dissipated. %t euilibrium, interstitialfluid pressure rises to microvascular hydrostatic pressure and interstitial colloid osmotic

pressure euals plasma colloid osmotic pressure, yielding a net filtration pressure of 2ero.

"he affected tissue is characteri2ed by large increases in water and protein content,fibrosis, and adipose cell deposition.

Copyright M ' by 8organ N Claypool 0ife Sciences.

. What is erythema?

Erythema means reddeningP of the s$in due to inflammation which is usually a result of

accumulation of cells of the immune system and chemicals these cells release. "here canbe many reasons for the occurrence of erythema7 exposure to heat, insect bites, infections,

allergy, non-ioni2ing radiation (sunlight, A) and ioni2ing radiation (Q-ray, nuclear

radiation). Exposure of the s$in to high doses of ioni2ing radiationleads to accumulationof lymphocytes in the layers of the s$in caused by the effects of cell death and eventually

to the development of erythematous s$in changes. Erythema induced by ioni2ing

radiation is infreuently seen in practice. 6eneral practitioners and dermatologists, whoare usually the first physicians to examine patients with these s$in changes, should be

familiar with radiation-induced erythema and a history of a relatively recent radiological

procedure is important to recogni2e. =atients may not be aware that the radiologicalprocedure he;she has had can lead to erythema and therefore, may not provide a historyof recent radiological procedures unless specifically as$ed. #n some cases, the

dermatologist may not recogni2e radiation as the cause of the s$in changes and proper

diagnosis may be delayed, sometimes with serious conseuences for the patient.

S$in cancer as a result of radiation exposure is not a maDor concern but deterministicinDury as described above is.
https://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/erythema.htm#ERY_FAQ03https://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/erythema.htm#ERY_FAQ03


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Page Top

2. Which are the most likely sites for erythema to occur?

5adiation-induced s$in inDury may occur on any part of a patientPs body. #ts appearance

and severity depends on the circumstances surrounding the radiation event and patient

specific factors such as smo$ing, poor nutrition, disorders of immune system (such aswith cancer, or treatment of cancer or chronic infections), obesity and the presence of

s$in folds. "herefore, the preexisting condition of the patient and the s$in prior to

irradiation is of great importance. S$in that is previously compromised from previousirradiation, chemotherapy, steroid use, or surgery is more prone to radiation inDury.

1ifferent parts of the s$in also demonstrate different levels of sensitivity to radiation. "he

s$in on the anterior surface of the nec$ is the most sensitive region. Other sensitive bodyparts are (in descending order of sensitivity)7 flexor surfaces (the Rfront of the forearms

or upper arms for example) of the extremities, the trun$, the bac$, the extensor surfaces

(Rbac$ of the forearm or upper arm for example) of the extremities, the nape of the nec$,

the scalp, the palms of the hands and the soles of the feet &Galter et al., '*.

Page Top

3. How much radiation dose to the skin is necessary to produce

erythema?

Erythematous reactions depend on numerous patient specific parameters that are difficultto predict with high accuracy. !or this reason, the minimum dose that might cause a s$in

change should not be expressed as a single threshold dose, but preferably as a threshold

that includes a range of doses&Galter et al., '*. =rompt s$in reactions may appearwithin a few hours after acute exposure to radiation with a s$in dose exceeding gray

(6y) for the range of radiation energies encountered in Q ray machines used for

interventional procedures. #n radiation therapy a s$in dose of F to + 6y with $A is

reuired for erythema to occur. 5adiation of higher energies reuires larger doses toproduce the same degree of erythema, since in these cases the maximum dose is received

in deeper tissues below the s$in. #n actual practice the s$in dose in interventional

procedures varies over the body, and it is the dose to the area with the highest s$in dose(pea$ s$in dose 9 =S1) that determines whether erythema will occur.

!or more information see7C5=, *

Page Top

4.What skin effects are possible at different doses?

S$in, fat below the s$in (subcutaneous fat), muscle and hair comprise the superficialtissues that are affected by radiation during medical exposures. "he severity of radiation

effects depends on the patient (underlying defects in 1J% repair, s$in integrity before

irradiation, health status as noted above) and on exposure specific parameters (dosefractionation, total dose, irradiation field si2e). 1epending on the time of appearance after

irradiation, s$in inDuries may be classified as prompt (hours to days), early (days to

wee$s), midterm (wee$s to months) or long term (months). Excluding patient specificfactors, the severity of the inDuries depends on radiation dose to the s$in.
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%t s$in doses up to approximately 6y, no harmful effects are expected to be observed

unless there has been prior irradiation of the s$in. #n the dose band of - 6y transient

erythema may be a prompt reaction to radiation exposure. Epilation (hair loss) that healsin the midterm may also be observed.

Getween and ' 6y epilation appears as an early reaction. !or doses at the upper band

limit, permanent partial epilation may be observed in the mid-term. 0ong term dermal

atrophy or induration is also possible.

%t doses between ' and ' 6y, dry or moist desuamation (s$in loss) may develop as an

early symptom. =rolonged erythema and permanent epilation in the midterm may befollowed by telangiectasia (an abnormal collection of small blood vessles), dermal

atrophy or induration in the long term. !or doses exceeding ' 6y, edema (s$in swelling)

and acute ulceration may appear as prompt reactions. Epilation and moist desuamationoccur early after irradiation. #n the midterm, if desuamation does not heal, a secondary

ulceration may occur. 1ermal necrosis that reuires surgical intervention appears at

higher doses. #n the long term, telangiectasia, dermal atrophy or induration and secondary

s$in brea$down are probable. Surgical treatment may be reuired if a persistent woundprogresses into a deeper lesion.

Aery serious reactions may occur for very high s$in doses exceeding + 6y.

!or more information see7&Galter et al., '*

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5. Will multiple interventional procedures increase the risk of

erythema?

"he general answer to this uestion is yesP.

owever, splittingP the delivery of a particular amount of ioni2ing radiation (also $nown

as fractionation) over multiple sessions can also reduce the possibility erythema

occurrence and its severity that would be seen if the entire dose was received at one time.5adiation effects tend to be cumulative, with the possibility of repair in-between two

consecutive exposures. #f there is a time gap between two interventional procedures,

repair processes enable the s$in to tolerate higher levels of radiationT the repair processesdepend upon the time gap and the number of times the radiological procedure is repeated.

owever, data from animal studies indicate that increasing the time gap beyond 3 hours

has no effect on the total dose for erythema to occur. "here is a lac$ of scientific evidenceon the exact relationship between dose effects and Q ray irradiation in the diagnostic

range. #nformation on s$in repair is primarily available in relation to high energyradiation as is used in radiotherapy. !or example, with three fractions administered at

$A, the erythema dose is '' 6y instead of the F - + 6y from a single dose at the same $A. :ith ' fractions, a total dose of 'F. 6y is necessary, and with / fractions, a total

dose of F 6y is reuired to induce the same effect. 5epair of inDury between fractions is

responsible for these differences and the increase in tolerance of the s$in to the radiation."he single dose to cause s$in necrosis is estimated at 6y. :hile these figures may not

be valid for diagnostic Q rays, the principle remains valid.
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Page Top

. How soon can one e!pect to see radiation"induced erythema in

the clinical practice of radiolo#ical interventional

procedures?

%s is the case when discussing radiation doses, the time after irradiation needed forerythema to occur should be expressed as a range &Galter et al., '*. #n a few caseswhere doses are very high, erythema can be observed a few hours after irradiation. "his

timing ma$es the recognition of the possible lin$ between the irradiation and s$in

symptoms easier, but this situation is rare.

#n most cases there is a delay between the induction of the inDury and the recognition ofsymptoms &:agner, *. "ypically about two to three wee$sP time is reuired before

symptoms emerge, and three to four wee$s before the symptoms are sufficiently irritating

for the patient to see a doctor. "hus, if not informed in advance, physicians and patients

do not usually associate the s$in reaction with a radiological procedure. !or furtherinformation on the different stages of erythema,please clic$ here

Page Top

$. %hould all patients under#oin# interventional procedures be

e!pected to have risk of skin in&uries and asked to report

back for a skin check"up?

Jo. % systematic follow-upP chec$-up of all patients undergoing an interventional

radiology procedure is not necessary. Only patients who are suspected to have received

doses high enough to cause s$in inDuries should be followed-up. "his fact ma$es it mostimportant that each interventional facility $eeps accurate records of patient dose and

implement a rigorous uality assurance practice at all times. !urther, it is of utmost

importance that all patients undergoing such procedures be aware of the possibility ofs$in symptoms, so that they can report any s$in symptoms occurring in the relevant areas.

Other patients who reuire follow-up are those with conditions associated with higher

radiosensitivity e.g. ataxia telangiectasia. 8oreover, this awareness about the possibilityof erythema on the part of doctors performing radiological procedures and also among

dermatologists is essential. %n understanding of dose and information about the dose

delivered to the patient can be helpful in avoiding unnecessary follow-up or concern. "he

patient should be advised about the areas on the s$in of the bac$ (in cardiac interventions)where erythema might develop. "his is best given to the patient in writing in the form of

a letter or brochure that will inform the patient of what to loo$ for and remind them to

chec$ for possible complications from the irradiation event. "he patient should be as$ed

to examine himself or herself until about to / wee$s after the procedure for any s$inchanges in those areas. Some facilities place a follow-up call to the patient during this

time to as$ about s$in irritation and this is found to be effective in ensuring that a patientwho develops s$in irritation does not see$ medical help at a place where there may be a

chance of missing the correct diagnosis.

"he Society of #nterventional 5adiology guidelines for patient radiation dose

management recommend a wee$ s$in chec$ when the procedure has involved F
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minutes of fluoroscopy, which is considered a rough indicator of high dose

procedures&Stec$er et al., 4*.

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'. What approach can help to dia#nose radiation"induced erythema

after a radiolo#ical procedure?

#n clinical practice, the diagnosis of radiation induced erythema may be either extremelydifficult if it is not recogni2ed by the medical professionals caring for the patient (as has

been the case in many patients in the past) or very easy, if the association between the

radiological procedure and the s$in changes is made.

"he worst situation may occur when the patient has not been informed at all about

possible s$in effects, and when little or no follow-up of any $ind is planned. #n such asituation, the patient leaves the facility with no $nowledge about the potential s$in

effects. #f an effect develops, the patient is less li$ely to associate it with the procedure

that was performed previously. #f the patient see$s medical help for the erythema, the

physician might not reali2e that the radiological procedure could have caused the effectand will loo$ for other diagnoses, all of which would be incorrect. Care will be delayed

and rather misplaced. "he literature reports on many cases in which wee$s have been lost

in trying to put a name on strange and unusual s$in lesions presented by a patient, with asuccession of ineffective therapies. Everything should be done to avoid such situations.

!inally, if health care professionals fail to recogni2e the cause and effect between

irradiation and s$in changes, the facility will have no feedbac$ that this has occurred,leaving the interventionalist to incorrectly assume that he or she used safe practice, when

in fact, this was not the case.

On the other hand, the diagnosis becomes much easier if the patient has been provided

with a brochure providing information about the possibility of s$in symptoms (reddening,itchy s$in changes) in the area treated. #n such a situation, he;she can report immediately

to his;her interventionalist, who will easily identify the lin$ with the radiological

procedure. #f the patient see$s the advice of a dermatologist or of any physician, he;she

will be able to then mention his;her recent radiological procedure as possibly responsiblefor such a s$in lesion, and this will help the physician to identify the direct lin$ between

the irradiation exposure and the s$in erythema.

"heappearance of s$in erythemais uite typical in that the s$in changes draw a precise

outline of the exposed areas.

!or more information see7&:agner, *

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(. How can erythema be treated?

0ocal management of erythema remains a matter of discussion, with some controversy

and on-going scientific investigation.
http://www.sirweb.org/clinical/cpg/Patient_Radiation_Dose_Management_Stecker.pdfhttp://www.sirweb.org/clinical/cpg/Patient_Radiation_Dose_Management_Stecker.pdfhttps://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/erythema.htm#tophttp://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/phaseserythema.htmhttp://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/phaseserythema.htmhttp://www.biij.org/2007/2/e22/http://www.biij.org/2007/2/e22/https://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/erythema.htm#tophttp://www.sirweb.org/clinical/cpg/Patient_Radiation_Dose_Management_Stecker.pdfhttps://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/erythema.htm#tophttp://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/phaseserythema.htmhttp://www.biij.org/2007/2/e22/https://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessionals/5_InterventionalCardiology/erythema.htm#top


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"he first (transient) early phase usually does not reuire any treatment, and freuently

subsides before any therapy can be started.

"he second erythema phase (if correctly recogni2ed) usually reuires some prescription

medication. One of the most popular therapies is %loe Aera, given in lotion or ointmentform. %lthough it has not been proven very effective in radiotherapy induced erythema,

nor shown to be superior to other ointments or creams through several trials, it remains a

freuently prescribed treatment.

Giafin cream is also freuently prescribed, particularly by the radiotherapy community.

owever, there is no randomi2ed trial supporting its use. #ts use is actually uestioned bysome authors.

"rolamin has been tested in several trialsT no advantage was found for its use in a series

of 3 patients irradiated for cancers of the head and nec$&Elliott et al., F*. One trial

showed superiority over Giafin, but another showed inferiority over Calendula.

Calendula Officinalis is one of the rare treatments of early phase s$in reactions for whicha clear advantage (versus "rolamin) has been demonstrated in a randomi2ed trial7 3

patients irradiated for breast cancer were randomly assigned either to Calendula local

therapy ('F Cases) or to "rolamin ('+). "he incidence of grade radiodermatitis was

less with Calendula (3' L) than with "rolamin (F/ L) (pK.')&=ommier et al., 3*.

0ocal steroids (ointments) are also commonly used &GostrUm et al., '*, but arandomi2ed trial &Schmuth et al., *has not indicated much success in using this

therapy as a prevention of radiation-induced erythema in radiotherapy. "his treatment

may however help reduce the inflammatory reaction.

yaluronic acid may be a possible treatment of early radiation-induced s$in reactionsT a

double-blind, randomi2ed trial &0iguori et al., '44*has shown that the prophylactic useof a cream with hyaluronic acid was able to reduce the incidence of high-grade

radiodermatitis compared to a placebo.

:hen the level of inDury reaches moist desquamation, eosin and anti-pain therapies are

usually necessary, combined with antibiotics and steroids in selected cases that reuirethem.

8anagement of necrosisexceeds the scope of this document. "he management of large

areas of radiation-induced necroses is usually difficult and should be managed by

experienced teams, and may reuire s$in grafting.

0arge excisions of the necrotic tissue and surrounding tissue are needed as there is nochance of recovery. Such excisions may be increasingly guided by imaging such as 85#.5econstruction of the soft tissues in the affected area may reuire autologous s$in grafts,

but may necessitate in some cases much more sophisticated approaches (such as grafting

of artificial dermis in an intermediate phase, musculo-cutaneous rotational or freeP flaps,epiploVc flaps, etc.).

Page Top
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). *re some patients at #reater risk for radiation in&ury than

others?

Some rare health conditions related to defects in 1J% repair genes render patients highly

sensitive to radiation. =atients with the hetero2ygous form of the ataxia telangiectasiagene have been found to be afflicted by unanticipated serious s$in inDuries &ymes et

al.,F*. Other genetically established anomalies such as !anconi disease, Gloomsyndrome, xeroderma pigmentosum, familial polyposis, 6ardner syndrome, hereditarymalignant melanoma and dysplastic nevus syndrome were found to be associated with

increased radiation sensitivity &Galter et al., '*.

1iseases such as collagen vascular diseases and diabetes mellitus are also suspected in

rendering patients more susceptible to radiation induced s$in inDury.

"he reasons why some patients with collagen vascular disease are more sensitive to

radiation are un$nown. 8oreover, having the disease does not systematically predisposepatients to heightened sensitivity. Only a few patients with collagen vascular disease have

been identified as having greater radiation sensitivity.

1iabetes compromises the vascular supply and this leads to a greater ris$ for long-term

complications. :hether or not the s$in type of an individual is correlated with sensitivity

for radiation induced erythema is still a matter of discussion.

+dema ,radin#

!ormerly called hydropsy or dropsy, edema is the abnormal accumulation of fluid inside

the interstitium and is clinically explained as being a swelling. #nterstitium refers to body

cavities (one or more) or locations underneath the s$in. 6enerally, the balance ofhomeostasis is what determines the interstitial fluid amount. #mpaired removal or

increased secretion of this fluid is what results in edema.

"here are many types of edema and edema grading generally depend on the depth and

duration of the dent.
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-lassification of +dema

Edema "ypes Description

Cutaneous edema #t occurs when a small area gets pressuri2ed and theindentation continues even after the pressure is removed.

Peripheral pitting

edema

#t is a common type which comes about when there is water

retention and can be caused by various conditions li$e heart

failure, pregnancy or diseases.

Non-pitting edema #t is where indentation is not persistent and is associated

with conditions li$e myxedema, lipedema ad lymphedema.

+dema ,radin#

Edema generally accounts for ten to thirty percent of bodyweight. owever, in severe

$washior$or cases, the proportion can even reach L.

=itting edema is graded on a scale of one to four. "he scaling depends on both the Rpit

leaves and depth and how long the pit will remain.

,radin# ethod / 0ent 0epth and 0uration

Grade Definition

1+ mm or less7 slight pitting, no visible distortion, disappears

rapidly.

2+ -3mm indent7 somewhat deeper pit, no readably detectable

distortion, disappears in '- seconds.

3+ 3-Fmm7 pit is noticeably deep. 8ay last more than a minute.

1ependent extremity loo$s swollen and fuller.

4+ F-+mm7 pit is very deep. 0asts for - minutes. 1ependent


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extremity is grossly distorted.

Source6uelph 6eneral ospital Congestive eart !ailure =athway

,radin# ethod 2/ 0ent 0epth and 1ebound ime

Grade Definition

'W "hree is a barely detectable mm depression. #mmediate

rebound

W "here is a 3mm deep pit. % few seconds to rebound.

/W "here is a Fmm deep pit. '-' seconds to rebound.

3W "here is an +mm deep pit (very deep). X seconds to

rebound.

Sourceogan, 8 () 8edical-Surgical Jursing (nd ed.). Salt 0a$e City7 =rentice

all

,radin# ethod 3/ verall %everity of +dema

"here are three grades of bilateral pitting oedema, and when it is not present, the grade isRabsent. Gilateral pitting oedema grades are classified using plus signs7

Grade Definition

1+ 8ild7 Goth an$les;feet

2+ 8oderate7 Goth feet, hands, lower arms and lower legs

3+ Severe7 6enerali2ed bilateral pitting oedema, which includes

both legs, arms, feet and face.

Sourcehttp://www.unicef.org/nutrition/training/3.1/20.html

:atch a video for pitting edema7
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Edema Patophysiology