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Hypoxic injury causing oncosis and acidosis
Secondary hypoxic injury occurs due to: hemorrhage, intravascular thrombosis, reduced blood flow from
inflammation following increased viscosity, increased intravascular pressure following hematoma and
muscle spasm.

Causes of secondary hypoxic injury are (1) anaerobic respiration - depending upon the susceptibility of
the involved tissues to hypoxia, glycolic pathways of ATP production lasts from few minutes to 6 h. During
+
+
aerobic respiration, ATP production is hampered, and acidosis occurs; (2) ATP dependent Na K ATPase
+
[5]
2+
+
pump failure - Na and Ca influx due to ATP dependent Na pump failure leads to cellular homeostatic
mechanism failure, leading to oncosis, cell death and necrosis.
Hypoxia leads to reduced ATP production. Hence, initial cryotherapy in musculoskeletal trauma is
beneficial, as cold helps reduce ATP demand.
Enzymatic (lysosomal) injury
Enzymes released from lysosomes of the injured and dead tissues: (1) acid hydrolases and phospholipases:
these enzymes lyse the cell membrane by cleaving the hydrocarbon chain of membrane phospholipids; and
(2) proteases: proteases inactivate protein by cleaving peptide bonds.

Effect of enzyme on tissues: acid hydrolases, phospholipase and proteases can cause loss of cell membrane
integrity and lead to increased hydropic swelling (oncosis) followed by cell death.

Also, trauma leads to inflammation and neutrophils are acute inflammatory cells and the first line of
cellular defense. Human neutrophil proteins (defensins; HNP-1 to 3) are bactericidal agents and interfere
[6]
with the function of smooth muscle cells in vessels, are prothrombotic, and may inhibit angiogenesis .
Updated secondary local tissue injury model
Mechanism of secondary ischemic injury to local tissue
The updated secondary injury model is based on improved biochemical understanding of tissue damage.
It has now been proven that ischemia resulting from vascular injury, rather than hypoxia, plays a more
significant role in driving secondary damage. Hypoxia poses only one problem of inadequate oxygen
supply, whereas ischemia presents with three possible consequences : (1) hypoxia - leads to anaerobic
[2]
respiration and thus reduced ATP (adenosine triphosphate); (2) low glucose supply to tissues, leading to
reduced ATP; and (3) acidosis that causes reduced cellular ability to produce ATP.

Hypoxia also affects mitochondrial function and leads to neural tissue damage as early as within 4 min ,
[5]
[7]
and musculoskeletal injury in approximately three hours .
Mechanism for secondary direct cell injury to local tissue
There are four possible mechanisms for secondary direct cell injury to local uninjured tissues: (1) lysosomal
mechanisms (due to the release of destructive enzymes that require low pH for activation); (2) protein/
enzyme denaturation mechanisms (due to low pH); (3) membrane permeability mechanisms (due to failure
of sodium-potassium-ATPase pump) - this leads to cellular swelling; and (4) mitochondrial mechanisms
(due to power house failure).

All these mechanisms are basically due to two types of changes - hypoxic and enzymatic.

Lysosomal mechanisms
Lysosomes, the main digestive organelle in a eukaryotic cell, is packed with catabolic enzymes maintained
at an acidic intraluminal pH. Under physiological conditions, these highly destructive enzymes, such as