By continuing to use the site you agree to our Privacy & Cookies policy

Your browser seems to have cookies disabled. For the best experience of this website, please enable cookies in your browser.

Close

Your browser is no longer supported

For the best possible experience using our website we recommend you upgrade to a newer version or another browser.

Close

The formation of oedema. Part 2: cellular response to tissue damage

Sharon Edwards, MSc, RN, DipN, PGCEA.

Senior Lecturer, Department of Nursing and Midwifery, University of Hertfordshire

The first paper in this two-part series, The formation of oedema. Part 1: pathophysiology, causes and types, by Sharon Edwards, appeared in the September 2003 issue

The first paper in this two-part series, The formation of oedema. Part 1: pathophysiology, causes and types, by Sharon Edwards, appeared in the September 2003 issue

There are links between the development and formation of oedema and some of the common conditions observed in clinical practice. In-depth knowledge of oedema formation helps us to understand our practice better, and the interventions, management, prevention, and specialist care these types of patients require.

Oedema is the abnormal collection of fluid in the tissues, which can occur in the interstitial or intracellular spaces (Edwards, 2003). It can be the result of two processes:

- An increase in hydrostatic pressure

- Reduced oncotic pressure (oncotic pressure is osmotic pressure exerted by proteins).

The balance between filtration and absorption can be altered as a result of everyday occurrences or as part of a disease process. The former is the movement of fluid from the capillaries into the interstitial space, while the latter is the movement of fluid into capillaries from the interstitial space (Germann and Stanfield, 2002).

Increase in hydrostatic pressure
Oedema forms when there is an increase in hydrostatic pressure either at the arterial end of the capillary or at the venous end. This raises the pressure of blood in the capillary and causes an increase in the rate of filtration (Edwards, 2003).

This will occur, for example, if hydrostatic pressure increases by 5mmHg - from 38mmHg to 43mmHg in the arterial end and from 16mmHg to 21mmHg in the venous end - but when oncotic pressure remains the same at 25mmHg. The differences in hydrostatic pressure between the extracellular fluid and the interstitial fluid at the arterial end of the capillary will be 43 - 1 = 42, and at the venous end 21 - 1 = 20. The net filtration pressure is 42 - 25 (the oncotic pressure of plasma) = 17mmHg at the arterial end, and 20 - 25 = -5mmHg at the venous end.

This leaves a deficit pressure of 12mmHg (which is the result of adding 17 to -5), leading to an increase in filtration and a reduction in absorption. As the lymphatic system drains only a certain amount of fluid, large amounts of fluid will collect in the interstitial space and cause the formation of interstitial oedema (Figure 1).

Immobility - When a person stands up, capillary hydrostatic pressure increases in the lower parts of the body because the column of blood raises hydrostatic pressure in the lower arteries and veins. When someone stands very still the problem is exacerbated because the inactivity minimises the action of the skeletal muscle pump, causing pressure in the lower veins to rise further, owing to venous pooling, in turn augmenting an increase in capillary hydrostatic pressure.

Hypertension - When blood pressure increases, the individual is at risk of developing oedema, as the increase in blood pressure is reflected through the circulatory system at the capillaries as the hydrostatic pressure. As such, this increases filtration and reduces absorption processes.

Peripheral vascular disease - When the pressure increases in the legs as a result of PVD, the principles outlined above will apply, leading to oedema and serious swelling of the legs. An increase in swelling can lead to hypoxic cell damage or stimulation of the inflammatory response (see below).

Heart failure - The pressure can rise in either the systemic veins or pulmonary veins, depending on which side of the heart is affected (Carelock and Clark, 2001). Failure of the left ventricle will cause pressure to rise in the pulmonary veins and can lead to oedema formation in the lungs, known as pulmonary oedema. Right-sided heart failure (complete heart failure) is characterised by an increase in hydrostatic pressure in the vena cava and other systemic veins. This tends to cause oedema in systemic tissues, and oedema will form in areas such as the wrists and ankles.

Renal failure - Certain types of damage to the kidneys will interfere with their ability to eliminate excess water and solutes into urine, resulting in accumulation of excess fluid in the body (Edelstein et al, 1997). Blood volume increases and blood pressure rises throughout the cardiovascular system. The increase in pressure raises capillary hydrostatic pressure, in turn increasing filtration and reducing absorption processes, leading to oedema.

Reduced oncotic pressure
Oedema also forms when there is a reduction in plasma proteins in the extracellular fluid. So any condition that leads to a reduction in plasma proteins will promote changes in capillary absorption. For example, if the oncotic pressure on the arterial side were to fall by 5mmHg from 25mmHg to 20mmHg - and the same level is reflected at the venous end - changes will occur.

The hydrostatic pressure in the extracellular fluid capillary is 38mmHg and in the interstitial fluid is 1mmHg. Thus, 38 - 1 = 37 and 16 - 1 = 15; arterial hydrostatic pressure and venous hydrostatic pressure become 37mmHg and 15mmHg respectively. At the arterial end this gives 37 - 20 = 17 and at the venous end 15 - 20 = -5, leaving a net deficit of 12mmHg and an increase in filtration, but a reduction in absorption, leading to accumulation of fluid in the interstitial space (Figure 2).

This occurs in the following conditions:

- Liver failure. The liver manufactures plasma proteins. Liver damage can cause plasma protein concentration to decrease, lowering plasma oncotic pressure. This can lead to formation of ascites.

- Renal disease. Kidney damage can increase elimination of plasma proteins in the urine - nephrotic syndrome. This loss of protein triggers a reduction in capillary absorption because of the drop in plasma oncotic pressure.

- Malnutrition. Malnutrition causes insufficient amounts of proteins to be digested through the gastrointestinal tract (Edwards, 2000). If the malnourished state is allowed to continue, the proteins stored in the body are broken down by the liver and used as a source of energy to maintain cellular and organ function. This leaves inadequate amounts of protein in the plasma to produce effective plasma oncotic pressure.

The inflammatory response
Oedema that occurs with issue injury and infection differs. The tissue damage leads to cellular changes, which cause a severe inflammatory response that ends with repair to damaged cells and tissue (Huddleston, 1992).

Following damage, the injured endothelium releases mediators and stimulates the clotting cascade. The mediators of inflammation are histamine, kinins, prostaglandins, complement and the cytokines. They act as a signalling system - chemotaxis - to attract nutrients, fluids, clotting factors and neutrophils and macrophages to the damaged site. The mediators cause a localised increase in capillary permeability, leading to swelling, oedema, redness, heat and pain - classic signs of inflammation (Marieb, 2001).

The tissue swelling observed in inflammation occurs due to a reversal of normal capillary absorption processes. This is because the damaged capillaries and injured tissues release mediators, allowing protein-rich fluid to leak out from the plasma into the interstitial fluid. As a result, the concentration of proteins in the interstitial fluid rises to a greater level than in the capillaries, increasing oncotic pressure in the tissues. In this way absorption occurs outward - from the plasma into the interstitial space - resulting in oedema.

Lymphatic obstruction
The lymphatic system normally absorbs interstitial fluid and the few proteins that normally pass across the capillary membrane. When the lymphatic channels are blocked by infection or neoplasms, or are surgically removed, proteins and fluid accumulate in the interstitial space. For example, lymphoedema of the arm or leg occurs after surgical removal of axillary and femoral lymph nodes for treatment of carcinoma.

Intracellular oedema
Intracellular oedema occurs due to hypoxic injury, when the blood flow falls below a certain critical level required to maintain cell membrane viability. Intracellular oedema can occur when the swelling from interstitial oedema becomes so great that it cuts off blood supply. In this instance, the interruption in the supply of oxygenated blood to cells can result in cellular changes, which in turn can stimulate the inflammatory response.

Intracellular oedema can also occur as a result of:

- Generalised ischaemia (hypovolaemia)

- Ischaemia of an organ (acute tubular necrosis, myocardial infarction)

- Breakdown in skin integrity (pressure ulcers).

The above will all lead to hypoxic injury. The consequent interrupted supply of oxygenated blood to cells results in:

- Anaerobic metabolism and reduced stores of adenosine triphosphate (ATP), a substance that releases energy when it is broken down

- Cellular membrane disruption, which causes sodium and water to move into the cell (Figure 3).

Cellular energy production
Nutrients such as glucose and fatty acids, as well as oxygen, enter the cell across the cell membrane. Hypoxic injury results in an inadequate flow of nutrients and oxygen to the cell (Edwards, 2002). If tissue perfusion continues to be insufficient, hypoxia occurs and the cell resorts to anaerobic metabolic pathways to produce energy. This produces several changes in cell function. Mitochondrial activity is diminished due to a lack of oxygen for:

- Glycolysis, leading to the formation of lactic acid, which rapidly accumulates in high concentrations in the cell and blood, lowering the pH

- The electron transport train, leading to the formation of nitric oxide, leading to localised and sometimes serious vasodilatation.

The result of anaerobic metabolism is a reduction in the energy available for cell work.

Cellular membrane disruption
Without intervention, oxygen deprivation is accompanied by cellular membrane disruption, leading to electrolyte disturbance (Edwards, 2002). This is a result of the reduction in ATP. The high intracellular potassium and low intracellular sodium and calcium concentrations are maintained by the following active transport systems:

- The sodium/potassium adenosine triphosphatase (ATPase)-dependent pump

- The ATP-dependent calcium transport pump.

Without sufficient supplies of ATP the plasma membrane can no longer maintain normal ionic gradients across the cell membranes and the ATP-dependent sodium potassium and calcium pumps can no longer function.

This changes the ionic concentrations of potassium and sodium. Potassium leaks into the extracellular space and sodium, followed by water, moves into the cell, causing cellular oedema and an increase in intracellular oncotic pressure (Edwards, 2001). Increased sodium in the interior of cells results in water also entering the cell, driven by osmotic forces, causing cellular swelling and distortion, which may interfere with organelle function (Buckman et al, 1992).

The plasma membrane of cells becomes increasingly permeable to larger molecular weight proteins, not simply as a result of direct cellular injury but also as a result of the systemic intracellular energy debt. The cell may eventually burst.

This influx of calcium into the cell is toxic, as the alteration in channel permeability and reversal of the calcium pump mean that the excess can no longer be pumped out. As a result, calcium accumulates in the mitochondria, causing structural derangement of the organelles, and may cause irreversible cellular injury, eventually leading to cell death (Hunter and Chien, 1999).

If the immediate interventions of fluid replacement and oxygen are not initiated, intracellular acidaemia becomes extreme, and cellular dysfunction becomes intemperate. The lysosomes, which break down intracellular waste, start to use their own structural phospholipids as a nutrient source. Eventually, the lysosomal membrane ruptures, allowing the release of lysosomal enzymes into the cytosol, resulting in self-digestion of the cell.

The role of the stress response
One of the earliest responses to injury is the stress response, or neuroendocrine activation. The increased sympathetic activity stimulates a highly complex series of events that leads to stimulation of the peripheral sympathetic system and adrenal medulla (Tan, 1997). Numerous substances are released into the circulation, such as:

- Catecholamines (adrenaline, noradrenaline)

- Glucocorticoids (cortisol)

- Mineralcorticoids (aldosterone, angiotensin)

- Pro-inflammatory cytokines.

The stress response is linked to:

- A reduction in protein (effects of cortisol)

- An increase in blood pressure (owing to adrenaline and noradrenaline release)

- Stimulation of the inflammatory response (cytokines)

- An increased demand for oxygen by body cells (increased cellular metabolism).

All of these are in some way implicated in the development and formation of oedema.

Conclusion
Oedema forms when fluid is allowed to move from one body fluid compartment to another. This is generally the result of an underlying condition.

There are two main forms of oedema - interstitial and intracellular:

- In interstitial oedema, a number of common pathways can be identified, caused by changes in capillary dynamics (hypertension, heart failure, malnutrition, renal disorders), blocked lymphatic system (cancer), or by stimulation of the inflammatory response (trauma, injury, infection)

- Intracellular oedema results in a lack of oxygen supply to cells (such as with pressure ulcers or myocardial infarction), leading to cellular hypoxia. Alterations occur to the plasma membrane due to the reduction in adenosine triphosphate.

The two types of oedema formation are not mutually exclusive, as the development of one can lead to formation of the other. An accumulation of fluid in the interstitial space or in the cells can destroy adjacent healthy cells and prevent regeneration of damaged tissues. The whole process can be exaggerated by the stimulation of the stress response, further stimulating inflammation, resulting in increased damage and a worsened condition.

Buckman, R.F., Badellino, M.M., Goldberg, A. (1992)Pathophysiology of hemorrhagic hypovolemia and shock. Trauma Quarterly 8: 4, 12-27.

Carelock, J., Clark, A.P. (2001)Heart failure: pathophysiologic mechanisms. American Journal of Nursing 101: 12, 26-33.

Edelstein, C.L., Ling, H., Schrier, R.W. (1997)The nature of renal cell injury Kidney International 51: 5, 1341-1351.

Edwards, S. (2000)Maintaining optimum nutrition. In: Manley, K., Bellman, L. Surgical Nursing: Advancing practice. Edinburgh: Churchill Livingstone.

Edwards, S. (2001)Regulation of water, sodium and potassium: implications for practice. Nursing Standard 15: 22, 36-42.

Edwards, S. (2002)Physiological insult/injury: pathophysiology and consequences. British Journal of Nursing 11: 4, 263-274.

Edwards, S. (2003)The formation of oedema. Part 1: pathophysiology, causes and types. Professional Nurse 19: 1, 29-31.

Germann, W.J., Stanfield, C.L. (2002)Principles of Human Physiology. San Francisco, Ca: Benjamin Cummings.

Huddleston, V. (1992)The inflammatory/immune response: implications for the critically ill. In: Huddleston, V. (ed.). Multisystem Organ Failure: Pathophysiology and clinical implications. St. Louis, Mo: Mosby Year Books.

Hunter, J.J., Chien, K.R. (1999)Signalling pathways for cardiac hypertrophy and failure. New England Journal of Medicine 341: 17, 1276-1283..

Marieb, E.N. (2001)Human Anatomy and Physiology (4th edn). Redwood City, Ca: Benjamin Cummings.

Tan, I.K.S. (1997)Metabolic response to illness, injury and infection. In: Oh, T. E. (ed.). Intensive Care Manual (4th edn). Oxford: Butterworth Heinemann.

Have your say

You must sign in to make a comment.

Related images

Related Jobs

Sign in to see the latest jobs relevant to you!

newsletterpromo