What are the phases of a frostbite injury cascade?

Updated: Oct 13, 2020
  • Author: Bobak Zonnoor , MD; Chief Editor: Dirk M Elston, MD  more...
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Heat conduction and radiation from deeper tissue circulation prevents freezing and ice crystallization until the skin temperature drops below 0°C. Once tissue temperature drops below 0°C, cutaneous sensation is lost and the frostbite injury cascade is initiated. This cascade comprises the following four phases, which may overlap:

  1. Prefreeze phase - This phase consists of superficial tissue cooling, which results in the increased blood viscosity, microvascular constriction, ischemia, and endothelial plasma leakage that precede the formation of ice crystals

  2. Freeze-thaw phase - This phase consists of ice crystal formation, more in the extracellular space than in the intracellular space.  Thawing may induce reperfusion injury with an inflammatory response.

  3. Vascular stasis phase - This phase consists of arteriovenous shunting at the margin between injured and noninjured tissue. Vasoconstriction may alternate with vasodilation. This may result in a combination of both progressive microvasculature erythrocyte sludging, stasis, coagulation, and thrombus formation, and leakage of blood from the vessels.

  4. Late progressive ischemia phase - This phase consists of thrombus-induced inflammation, hypoxia, and anaerobic metabolism leading to tissue necrosis

Initial injury is mediated by extracellular-tissue ice crystal formation. These crystals damage the cellular membranes, initiating the cascade of events that cause cellular death. As freezing continues, a shift in intracellular water to the extracellular space leads to dehydration, increased intracellular osmolarity, and eventually, intracellular ice crystal formation. As these ice crystals form and expand, the cell undergoes mechanical damage, which is irreversible.

Damage also is caused by a cycle of vascular changes referred to as the hunting reaction, which involves alternating cycles of vasoconstriction and vasodilation. Vasoconstriction with associated conservation of heat is maximal at approximately 15°C. As exposure to lower temperatures continues below 10°C, the hunting reaction causes alternating vasoconstriction and vasodilation, which warms the exposed affected tissues and slows the rate at which extracellular and intracellular ice formation occurs.

Frostbite of peripheral tissues is delayed by the extraction of heat from the body’s core. This process is helpful in relatively warm and insulated situations but is potentially deadly if it accelerates core heat loss. [19] The hunting reaction has been examined extensively by studies comparing Caucasians with Japanese patients [20] and healthy individuals with those who have Raynaud disease. [21] In addition, it has been evaluated with regard to sex, season, and environmental temperature. [22]

When the hunting reaction stops at colder temperatures, vasoconstriction persists uninterrupted. This invariably leads to hypoxia, acidosis, arteriolar and venular thrombosis, and ischemic necrosis. Prostaglandin F2 and thromboxane A2,which are released during the course of freezing and thawing, potentiate vasoconstriction, platelet aggregation, and thrombosis.

Various authors have compared the effects of quick freezing and slow freezing at the microscopic level. Rapid freezing is thought to increase intracellular ice formation superficially, whereas slow freezing causes deeper and more extensive cellular injury by causing freezing of water in the intracellular and extracellular spaces. Because extracellular freezing progresses more rapidly than intracellular freezing, osmotic shifts occur. These shifts cause intracellular dehydration, which decreases the viability and survival of individual cells.

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