An agent may cause necrosis by acting directly on the tissues, or may do so indirectly by interfering with their blood-supply or innervation.

Instances of Direct action are afforded by chemical agents, by morbid poisons, by traumatic action, and by extremes of temperature.

Chemical agents, such as strong acids or alkalies, destroy the vitality of the tissues by their caustic action, and they sometimes dissolve the tissues at the same time.

Toxines evolved by microbes frequently produce necrosis. The products of ordinary putrid decomposition may do so, as where decomposing urine is extravasated into the tissues. We see also in the cases of pyaemia, erysipelas, tuberculosis, syphilis, diphtheria, that when microbes settle in the tissues and multiply, they commonly give rise to necrosis when acting in a concentrated form.

Traumatic action, besides its direct effect in injuring the tissues, produces necrosis by obstructing or rupturing the vessels.

Extremes of heat or cold produce necrosis, partly by affecting the living structures directly, and partly by their effect on the vessels. The ear of a rabbit, which has been ligatured at its base and immersed in water heated to 130°-136° F., or in a freezing mixture, reduced to about 0° F., suffers necrosis even when the immersion is for a very short time, and the ligature is removed at once. If the temperature is less extreme a short immersion produces intense inflammation, and a longer immersion produces necrosis. (Cohnheim).

Pressure on a part produces necrosis when long continued, and it does so chiefly by emptying the vessels, and especially the capillaries. Pressure from within is exemplified in the case of abscesses and tumours which advance to the surface and cause sloughing of the skin. External pressure is seen to produce necrosis, in the case of bed-sores, or where bandages and splints, by pressing on a bony prominence, cause sloughing of the skin over it.

Obstruction of arteries is a frequent cause of necrosis. As the nutrition of the tissues depends on the capillary circulation, obstruction in an artery will scarcely produce necrosis, unless it brings about a complete stasis in the capillaries. (See under Embolism).

Besides obstruction of arteries by embolism, there is very frequently a partial interference with their calibre as a result of atheroma, especially when thrombosis is superadded. In senile gangrene there is always atheroma of the arteries of the lower limb, and this even without complete obstruction, may be the cause of gangrene, although weakness of the heart and of the tissues resulting from old age may contribute. Softening of the brain in old people is similarly produced from atheroma. These softenings are frequently in the cortex of the brain, and lead as much to weakness of mind as to motor paralysis whereas softening from embolism is usually central, and leads to more definite paralysis.

Spasm of arteries is an occasional cause of gangrene, as in Raynaud's disease (see further on). It has also been assigned as the cause of gangrene in poisoning with Ergot of Rye. In former days there used to be epidemics of what is now recognized as Ergotism from eating bread made with grain in which ergot was present. The symptoms consisted of disturbances of sensation and violent cramps, followed by redness of the skin, sometimes culminating in necrosis of the tips of the fingers and toes, or of the nose and ears. This result is ascribed by some to spasm of the arteries, a view which is confirmed by an observation of Recklinghausen, who found by experiment in fowls that under the influence of ergot the arterioles of the cock's comb and of the tongue showed a violent and persistent contraction, during which thrombosis occurred, obstructing or occluding their calibre. Besides this action on the vessels, the poison may have a directly poisonous effect on the tissues, and the necrosis may be further assisted by the injury to which an anaesthetic part is exposed.

Obstruction of veins seldom produces necrosis, as these vessels anastomose so freely that stasis in the capillaries will rarely occur. It takes place, however, when a piece of intestine is incarcerated in a sac with a narrow neck, as in a strangulated hernia, in which case gangrene is frequent. Even extensive thrombosis may lead to gangrene.

Nervous influences frequently contribute to the production of necrosis. Lesions of the peripheral nerves, the spinal cord and brain, are sometimes followed so rapidly by the formation of sloughs in parts of the body exposed to pressure in lying in bed, that the term Acute bedsore, or Acute decubitus, has been applied. This has been ascribed to an affection of the trophic nerves by the primary lesion, but it remains doubtful to what extent the immobility of the patient, his constant retention of the same posture, and the alteration in the circulation may account for the necrosis without calling in the action of trophic nerves.

A similar difficulty exists as to the necrosis in Anaesthetic leprosy. Here the affected parts are devoid of feeling and the vaso-motor nerves are implicated, hence the parts are more exposed to injury and to variations in temperature, which are not compensated by alterations in the circulation.

In all the forms of necrosis Weakness of the heart may exercise an influence, and in some cases it may even be the main element. In extreme cases of general weakness, and in some cases of specific fever, there may be necrosis of the extremities partly due to weakness of the heart and partly to alteration in the constitution of the blood.

The various tissues comport themselves somewhat differently in relation to the causes of necrosis, or, in other words, they are in different degrees able to survive a deprivation of blood. For example, Litten found that if he ligatured the renal artery in a rabbit for 1 1/2 to 2 hours and then removed the ligature, the circulation was perfectly restored, and the blood-vessels and connective tissue survived; while the epithelium of most of the convoluted tubules underwent necrosis. Ehrlich and Brieger found that a suspension for one hour of the circulation in the lumbar part of the spinal cord caused necrosis of the grey substance, while the white substance was not affected. Muscle seems also peculiarly sensitive to deprivation of blood. Thus in embolism of the coronary artery of the heart the muscular fibres die before the circulation can be re-established, while the connective tissue survives. In this relation, skin, bone, and connective tissue possess great powers of resistance, while nervous tissue, muscle, and the secreting tissue of glands are more vulnerable.

The tissues again may be rendered unduly susceptible of necrosis. Anaemia and passive hyperemia render the tissues more vulnerable. Diabetes has a similar effect; boils and carbuncles are common in that disease, and slight injuries are liable to go on to necrosis. Again, children who are in extreme states of inanition, especially after acute fevers, are liable to Cancrum oris or Noma in which extensive necrosis of the soft parts in the neighbourhood of the mouth occurs.