17. Tissue hypoxia, ischemia, reperfusion and tissue metabolism

Ischaemia reduces the oxygen supply to cells. This causes them to switch to anaerobic metabolism, which produces much less ATP. The Na+/K+ ATPase dysfunctions, causing Na+ to enter the cell. As a result Ca2+ also enters. Intracellular calcium damages the mitochondria and activates many destructive enzymes. Damaged mitochondria produce more reactive oxygen species, especially during reperfusion.

Ischaemia

One of the major consequences of shock is that the tissues don’t get enough oxygen and nutrients, a condition known as ischaemia. This begins a cascade of bad things that can eventually cause necrosis. The hypoxia causes the tissues to switch to glycolysis, which is anaerobic. This switch has two consequences: the tissues produce much less ATP than normal and lactic acid is produced, causing lactic acidosis.

Many enzymes are dependent on ATP to work, most notably the Na+/K+ ATPase which upholds the resting membrane potential. Water will start to enter the cells along with Na+, causing intracellular swelling and damage to the lysosomes and cell membrane. Lysosomal enzymes will be released out of the cell, damaging cells in the vicinity.

Because Na+ accumulates in the cell will the cell try to get rid of it by pumping out Na+ in exchange for Ca2+, which causes intracellular Ca2+ to also increase. Calcium enters and damages the mitochondria and activates proteases which cause further membrane damage. Due to the low energy crisis and membrane damage will cell metabolites leak out and cause an inflammatory reaction.

The thromboxane/prostaglandin ratio inside the cell increases, which also promotes swelling. The swelling of the cells may prevent reperfusion (see below), leading to the no-flow phenomenon.

Free radical formation

The hypoxia causes problems for the electron transport chain in the mitochondria. Reactive oxygen species are formed from the mitochondria and by activation of xanthine oxidase. These free radicals (especially superoxide ion) cannot be removed efficiently because of inactivity of superoxide dismutase (SOD) and glutathione peroxidase.

The complement system is activated by the cell debris of necrosis. When activated will it trigger further free radical formation.

The free radicals will damage cell membranes of not-yet damaged cells. They will also change the tertiary structure of protein by forming disulphide bonds, which impairs their function. DNA will also be damaged.

Intermediate metabolism

The presence of catecholamines, cortisol and growth hormone in shock inhibits the effect of insulin. The result is that the blood glucose level increases and muscle and adipose tissue doesn’t take up as much glucose. Lipolysis also increases, causing triglyceride and free fatty acid levels to increase.

Gluconeogenesis is supplied by protein and glycogen breakdown. The protein breakdown may affect respiratory and cardiac muscle.

Permeability

Permeability increases due to vasoactive molecules like histamine, bradykinin, serotonin and thromboxanes. Osmotically active products accumulate in the interstitium. The increased osmosis and permeability cause protein-rich fluid to leave the capillaries and enter the interstitium, causing oedema. When fluid leaves the capillaries will the plasma volume and capillary flow decrease, worsening the consequences of shock. The oedema impairs nutrient and O2 transfer to tissues.

With the impairment nutrient and oxygen transport, reduced capillary flow, local acidosis and hypoxia will the endothelium eventually take damage as well. Platelets love to adhere to damaged endothelium, meaning that the clotting cascade becomes activated and disseminated intravascular coagulation occurs.

Reperfusion

The word should be thought of as re-perfusion, meaning that a tissue that previously was ischemic suddenly regains its perfusion. You might immediately think that reperfusion is a good thing, but it isn’t always.

Reperfusion is beneficial if the ischaemia hasn’t lasted more than 15 minutes. In myocardial infarction, reperfusion of the infarcted tissue within the first 3 hours has the best prognosis. Reperfusion is safest when it occurs slowly and not suddenly.

If ischaemia has lasted more than 15 minutes reperfusion can be harmful. Because the cells are already close to death will the sudden influx of O2 increase the formation of oxygen free radicals. All the cells defence mechanisms against free radicals were reduced during the ischaemia, making the effects of the radicals even worse.