Factors Affecting Wound

FACTORS AFFECTING WOUND

HEALING

Dirk Lazarus

9 November, 1996

I. GENERAL HOST FACTORS

Age

Nutrition

Oxygenation

Disease

Immunocompetence

LOCAL FACTORS

Local blood supply (the most important factor)

Local infection

Presence of FB or devitalised necrotic tissue

Repeated trauma

Site of Injury

Radiotherapy

THERAPEUTIC FACTORS

Debridement and cleansing

Closure, suturing

Dressings

Immobilisation

Drugs

AGE

· Foetal wound healing is a different matter.

· Older patient may have slower healing, diminishes tensile strength and thicker scars.

· Cell multiplication, differentiation and production of substrates is slower.

· The defect is qualitative rather than quantitative.

· Concomitant disease may be more prevalent and impact on other factors.

· Children tend more towards keloid.

NUTRITION

· Protein-calorie malnutrition and specific nutritional deficiencies are important.

· Nutrition is affected by: intake, absorption, metabolism, etc.

· Nutrients:

Protein-calorie

CHO -energy

Fat -energy and cell membranes

Protein - for synthesis and repair of tissue

Vitamins

Vit C - collagen synthesis, fibroblast formation, superoxide formation, angiogenesis

Vit A - epithelialisation, anti cortisol, collagen deposition

Vit E-membrane stabilising properties

Minerals and trace elements

Zn - mitosis, collagen synthesis, important component of enzymes

Cu - collagen synthesis

Calcium

Magnesium

Phosphate -neutrophil activity

Selenium -immune system

OXYGEN

· A critical nutrient for the wound.

· Usually a wound has high metabolic (O2) demands at a time when it cannot be provided d/t inadequate vasculature. The wound therefore functions in a hypoxic environment. Wound healing can be greatly improved by incraeasing the O2 tension.

· Required for

free radical formation and bacterial killing

cell replication

protein synthesis and export

hydroxylation of proline and lysine

epithelialisation

angiogenesis

energy production

· Although WBC’s and fibroblasts can survive and function at low oxygen tension, they do so better in an environment with oxygen. At a higher oxygen tension, fibroblasts can replicate and produce collagen.

· Regenerating epithelial cells rely on O2, but cannot obtain this topically from exposure to the air because there is usually a layer of denuded exudate or eschar on the wound that acts as a barrier. They are therefore dependent on perfused vascular O2 delivery. Covering wounds with a non-permeable dressing, however, impedes epithelialisation (although it stimulates angiogenesis) whereas an O2 permeable occlusive dressing enhances epithelialisation.

· Angiogenesis is stimulated by hypoxia (the macrophages are triggered to produce angiogenesis factor)

· Infection occurs more commonly in hypoxic wounds. Keeping wounds well oxygenated is important in preventing wound infection. WBC’s can internalise bacteria in an hypoxic environment, but their ability to kill them is jeopardised. Killing mechanisms are either O2 dependent or O2 independent. The O2 dependent system is important as the other is insufficient to deal with the bacterial load. The killing ability induced by the toxic O2 free radical killing mechanism is directly proportional to the O2 tension. Usually the leukocytes’ O2 demands increases 10-20 times after phagocytosis so that oxidative killing of bacteria by free radicals can proceed.

· The commonest cause for poor wound healing or wound infection is inadequate O2.

· Most wound healing problems associated with DM, irradiation, atheroma, etc can be ascribed to poor O2 delivery to the wound. Hyperbaric O2 increases tissue oxygenation considerably as long as wound vessels are not obliterated, but cannot alter wound ischaemia in the absence of satisfactory perfusion.

· Oxygenation is dependent on general and local factors.

· General factors: Resp function, CVS function, intact vessels and absence of PVD, blood rheology, hydration, anaemia, smoking, pain, etc.

· Smoking:

smokers are prone to cardio-resp disease and PVD

carboxyhaemaglobin - CO shifts the Hb dissociation curve to the L, thus resulting in less tissue O2 delivery

nicotine acts directly on the vasculature to cause vasoconstriction for 50 minutes after a cigarette and it acts indirectly via the nervous system to cause vasoconstriction.

· But for flaps and in surgical patients, tissue perfusion is all important.

· Poor perfusion results in infection and subsequent flap loss.

· Hyperbaric O2 has been suggested as a mode of therapy for the failing flap, for diabetic ulcers, osteomyelitis, osteoradionecrosis, clostridial myonecrosis and other conditions.

Oxygen derived free radicals

· Production can be triggered by radiation, chemical agents, ischaemia, inflammation and reperfusion.

· Free radicals have a direct involvement in wound healing, but they can also damage tissue - they can cause cellular damage when released into the e/c matrix:

degrade hyaluronic acid and collagen

destroy cell membranes

disrupt organelle membranes

interfere with important protein enzyme systems

· Free radical scavengers can enhance flap survival:

SOD

Allopurinol (blocks XO)

· Free radical tissue damage has been implicated in

hyperoxygenation syndromes

ischaemia reperfusion injury

chemical induced tissue injury

drug induced haemolytic anaemias

Vit A and E deficiency states

ageing

DISEASE

· Multiple diseases can impact on wound healing:

1. Congenital:

a. connective tissue disorders (pseudoxanthoma elasticum, Ehlers Danlos, Cutis laxa)

b. enzyme deficiencies (lysyl oxidase)

2. Inflammatory: sepsis generally, locally or at a distant site

3. Vascular: PVD (arterial or venous), anaemia

4. Metabolic: DM, jaundice, uraemia, Cushings, etc

5. Neoplasia

Diabetes

Diabetics exhibit poor wound healing for a number of reasons.

Small vessel occlusive disease is no longer considered to be a component of DM.

Neuropathy

Decreased endo-neural blood flow with subsequent neuropathy is the prime cause of the problem in diabetics. Sensory neuropathy results in a failure of the diabetics early warning system; motor neuropathy causes alterations of pressure points.

Local ischaemia

This is not due to microangiopathy as was previously thought, but rather to large vessel disease and to haemorheological changes of blood. These haemorheological changes are due to the RBC membrane becoming stiff and non deformable d/t a non-enaymatic glycosylation of spectrin, a RBC membrane protein. The non-deformable RBC’s cause microvascular damage, increased RBC agglutination and increased blood viscosity. As viscosity increases, blood flow slows which serves to further increase viscosity d/t the thixotropic nature of blood. Hydrostatic pressure therefore increases to maintain blood flow which causes transudation of fluid, haemoconcentration and a further increase in viscosity. Transudation results in tissue oedema and poor oxygen delivery. Thus a functional ischaemic state occurs.

Increased susceptibility to Infection

Not only is humoral and cellular immunity impaired, but also body defences (skin, mucosa). Neutrophils and macrophages exhibit decreased chemotaxis and phagocytosis and lymphocytes decreased blast transformation and i/c killing. With regard to humoral immunity, there is decreased opsonic ability.

Prevention of wounds and infections is therefore important in diabetic patients. Tight control returns spectrin to normal within 24 hours and thus improve rheology. Bed rest reduces hydrostatic pressure, transudation and oedema and thus improves tissue oxygen delivery. Pentoxyfylline improves RBC deformability and may be of use. Weight control is beneficial. Vit A may aid wound healing in these patients.

In the established wound, if large vessel disease exists, revascularisation procedures and coverage with a well vascularised flap (even if hooked directly on to the vascular graft) have been shown to be of benefit.

IMMUNOCOMPETENCE

· May be affected by a host of diseases or therapeutic manoeuvres.

_ Congenital or acquired immune diseases

_ Malnutrition (excess or deficient)

_ Sepsis (general, local or distant)

_ Malignancy

_ Metabolic disease

_ Drugs: cytotoxics, steroids

_ Surgery

_ Radiotherapy

Steroids

· The effect of systemic corticosteroids on wound healing:

Monocytopenia, therefore ¯es the macrophage at the wound site

¯es fibroblast proliferation and thus collagen and matrix synthesis

¯es angiogenesis

¯es wound contracture.

NSAIDS

· Aspirin, ibuprofen have been shown to ¯ collagen synthesis by an average of 45% even at ordinary therapeutic doses. The effect is dose dependent and mediated via PG’s.

Chemotherapeutic agents

· ¯ circulating WBCs and impaired formation of granulation tissue.

· fibroblast proliferation and wound contraction.

· Chemotherapy should only be started 10-14 days after surgery to avoid having a detrimental effect on wound healing.

Radiation Therapy

· Radiation effects can be local or general; acute or chronic.

· Acute radiation causes stasis and occlusion of small vessels with a subsequent ¯ in collagen deposition and a ¯ in wound tensile strength. Local effect on endothelial cells.

· Radiation also has a direct inhibitory effect on fibroblast proliferation with possible permanent damage to fibroblasts.

· Whole body irradiation results in depression of the BM, the main effect being a monocyteocytopenia with ¯ed macrophages at the wound site.

· Chronic radiation damage is probably not primarily d/t tissue ischaemia.

· It is more likely d/t changes in the cell nucleus and resultant cytoplasmic malfunction.

Lathyrogens (BAPN)

· Beta-amino-propionitrile (BAPN, found in ground peas) and d-penicillamine prevent the formation of aldehyde intermediates in the cross linking process of collagen thus reducing the strength of collagen bundles.

· Can be used to control scar tissue.

OTHER FACTORS

Mechanical stress

Wounds subjected to TE while healing tend to have an ed tensile strength and better organised collagen at the expense of a stretched scar.

Temperature

Animals kept hypothermic take longer to heal and wound strength is reduced.

Denervation

No effect on epithelialisation or wound contraction.

High collagenase activity, however, renders the skin of plegic patients highly susceptible to the development of destructive ulcers.

Infection

Infection at the wound, regionally or at a distant site will impair wound healing.

Infection occurs when the number of orgs exceeds the tissue’s ability to deal with them.

For most bacteria this is when > 105 orgs per gram of tissue (Robson).

Beta haem step will establish infection at much lower numbers.

Sub-infective bacterial loads (<102 orgs per gram of tissue)seem to accelerate wound healing, whereas infection impedes it.

The effect of infection:

es PO2

es WBC chemotaxis, migration, phagocytosis and killing

epithelialisation and angiogenesis

More oedematous, haemorrhagic and fragile granulation tissue

es collagen lysis

Inhibitory effect on wound contraction

REFERENCES

SRPS

Dermatology Clinics 1993.

Clinics in Plastic Surgery 17(3), 485-501, July 1990