The damage evoked by frostbite stems from 3 distinct processes—extracellular and intracellular ice crystallization, intracellular dehydration, and arterial insufficiency with intermittent spasm.
Initial injury is mediated by extracellular-tissue ice crystal formation. Decreased temperature results in the formation of extracellular ice crystals. 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 further damage, which is mechanical and 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 conservation of heat loss maximizes at approximately 15ºC.
As exposure to lower temperatures continues below 10ºC, 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 the peripheral tissues is delayed by the extraction of heat from the organism's core, which is functionally helpful in warm, insulated situations but is potentially deadly if this process accelerates the core heat loss. For readers interested in a more detailed description of the hunting reaction, please refer to Dana et al's 1969 treatise in Archives of Dermatology.16 The hunting reaction has been examined extensively, comparing Caucasians and Japanese17 ; comparing healthy individuals and those with Raynaud disease18 ; and comparing sex, season, and environmental temperature.19
When the hunting reaction stops at colder temperatures, uncycled vasoconstriction persists. This invariably leads to hypoxia, acidosis, arteriolar and venular thrombosis, and ischemic necrosis. During the cycling of freezing and thawing, prostaglandin F2 and thromboxane A2 are released, which potentiates further vasoconstriction, platelet aggregation, and thrombosis.
Various authors have compared the effects of quick freezing and slow freezing at the microscopic tissue level. Rapid freezing is thought to increase intracellular ice formation superficially, while 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 does intracellular ice formation, osmotic changes occur; these changes cause intracellular dehydration, which in turn decreases the viability and survival of individual cells.
Some authors and textbooks from the 1980s have likened the microscopic changes in frostbite to ischemia-reperfusion injury. Much of our understanding of the chemical cascade of frostbite injury comes from this decade, where many studies documented inflammatory mediators, such as prostaglandins, thromboxanes, bradykinin, and histamine, in frostbitten tissue. However, agents that block these mediators have had only marginal clinical success.
A study of the subject was undertaken in 1998 by Zook and associates.20 Zook et al studied a live gracilis muscle preparation transilluminated and projected on a view screen that allowed long-term evaluation of freezing tissue. The authors specifically found that reperfusion of muscle after freezing was varied but that almost all circulation was restored 10 minutes after rewarming. Of greatest interest, they observed that the microcirculation blood flow resumed at near normal levels after rewarming, suggesting that the vascular structures were not damaged by the freezing as had been previously postulated.
The most significant damage was created by white clots and fibrin formation with associated microvascular thrombosis, which initially occurred at 5 minutes after rewarming and continued for as long as 1 hour after rewarming. Zook noted that platelet abnormalities and fibrin formation resulted in the greatest early and late tissue damage and that classic reperfusion injury did not seem to be as important a factor as previously believed. This may explain the varied results noted in the literature with attempts at modification of the mediators of ischemia-reperfusion injury, which do not affect platelets or fibrin formation.
The true effect of chemical mediators remains controversial; however, ischemia-reperfusion injury may still occur because of microvascular thrombosis at a later time, compounding the mechanical effects of ice formation and the chemical effects of platelet abnormalities and fibrin microvascular clot formation.
