Exacerbation of Inflammation by Aggressive Cold Therapy: Preventing Microcellular Ice Crystal Injury

Exacerbation of Inflammation by Aggressive Cold Therapy: Preventing Microcellular Ice Crystal Injury. An Alternative to Conventional R.I.C.E. Therapy

Stuart Tomares, M.D.


Exposure to sub-0°C temperatures has long been known to cause mammalian tissue damage and cell death (frostbite). The biological mechanisms of such injury were elucidated in the 1970s and 1980s in research into the viability of cold storage of embryos for in vitro fertilization. Those studies revealed that cells exposed to sub-0°C conditions formed microscopic intra- and peri-cellular ice crystals that were causal in cell injury and cell death. In this paper the mechanisms of ice-related injury and their association with the prolongation and exacerbation of inflammation will be examined. A novel cooling technology, utilizing thermal conduction regulation, will be suggested as a safer – and more effective and comfortable – alternative to existing R.I.C.E. cold therapy modalities.


Cells exposed to sub-0°C conditions show signs of damage at an ultrastructural level16. Ice crystals in and around cells have sharp corners and edges that act like razor blades around a balloon. In addition to such direct effects, freeze stress also induces signals for programmed cell death (PCD)19. Though Rest, Ice, Compression, and Elevation (R.I.C.E.) therapy is one of the most commonly recommended therapeutic modalities in the treatment of acute and chronic musculoskeletal injuries, little attention is paid to the potential for cellular injury from micro- and macroscopic ice crystal formation11,19.

Mechanisms of Injury and Collateral Damage

Three primary mechanisms of cellular injury are known to be associated with exposure to sub-0°C conditions. The first is simple direct mechanical disruption of the cell membrane by contact with small ice crystals shards formed in the extracellular matrix. Razor sharp microscopic ice crystals cut into cell membranes directly initiating an injury response; if numerous enough, cell membrane disruption from direct ice crystal contact can result in cell death, the main pathology in frostbite. The second mechanism is the formation of intracellular ice crystals with disruption of delicate organelles initiating a PCD4 cascade and the release of “help me” mediators (inflammation being the first step in response to such intracellular injury)11. Lastly, the formation of tiny ice crystals in the extracellular matrix results in an uneven solute concentration (high osmotic pressure) in the extracellular space, causing an efflux of water from aquaporins and cell desiccation injury and/or cell death. In all three pathways injured cells elicit an injury response, the first stage of which is inflammation. Though hyperemia and recruitment of leukocytes serve a number of beneficial functions in early host defense, this response can prolong inflammation in musculoskeletal injuries19. Cells injured by ice crystals release a multitude of proinflammatory mediators10,11,19 and promote the onset of an immune responses to antigens in the vicinity of injured cells, with surrounding tissues then infiltrated with leukocytes, consisting initially of neutrophils followed by accumulations of monocytes3,10.

Cells killed by freeze-thawing ex vivo stimulate robust inflammation when injected into animals1; signals arise from pre-existing cellular components that are passively released into the extracellular environment, including Fibrinogen, Collagen Derived Peptide, and Hyaluronic Acid. More recently it also was discovered that certain cellular components may activate the complement pathway by an indirect mechanism. Circulating IgM autoantibodies form immune complexes that activates complement and initiate an inflammatory response6,7,8. In all cases the common end result is the onset of inflammation in response to cellular freeze stress.

What About R.I.C.E. Therapy?

In the case of R.I.C.E. therapy for musculoskeletal conditions, there is often an acute and/or chronic inflammatory component to the existing injury. While cooling is effective at slowing the influx of pro-inflammatory cells and reducing the redness, pain, and swelling of existing inflammation, the potential for micro- and macroscopic ice crystal formation from conventional ice packs puts patients at risk of repeated cellular-level injury and repeated inflammatory cascade1,2. If one of the goals of R.I.C.E. therapy is to reduce overall inflammation and protect tissues from the deleterious effects of pro-inflammatory mediators19,21, then care need be taken to avoid sub-0°C tissue temperatures during cooling. It should be noted that even skin or subcutaneous tissue inflammation as a result of ice crystal-related injury can adversely affect deeper tissues as inflammation is poorly localized. Inflammation in nearby or peripheral tissues can result in a generalized influx of inflammatory mediators and leukocytes to tissues within proximity2,21. As such, even ice crystal formation in the skin (ice burn) from aggressive cold packs can result in an inflammatory response in the nearby ligaments and tendons.

The Dark Side of R.I.C.E. Therapy

In addition to the risk of new and exacerbated tissue inflammation associated with cold therapy-related ice crystals, there also is the risk of more severe tissue injury; reports of burns and deep tissue damage from excessively cold ice packs are not uncommon in the literature12,13,14,15,16,17,20,21,22,23, most seriously among the elderly population and young children15,18,23,24,25,28. Despite this, often little consideration is given to choosing an appropriate cold therapy device to reduce the risk of burns. Non-burn injuries to deep tissues also are not uncommon, including motor and sensory nerve palsy in young athletes27.

Fig.1 Frostbite from bag of ice chips applied directly to the foot.

Fig 2. Frostbite in 59 y/o woman resulting in 1% total body surface area burn (shown after graft).

Fig 3. Frostbite in 47 y/o woman from application of a frozen gel pack.

A Safer Alternative?

One novel approach to solving this problem is the übertherm cold therapy device, which utilizes a thermal conduction rate regulating material between the patient and the source of cold. These cold compression therapy devices target an energy conduction rate of approximately 0.2 watts per meter kelvin W/(m·K), reducing the risk of sub-0°C tissue conditions while allowing the slow cooling of deep tissues over time. This is accomplished by a series of conducting and insulating layers in series that are woven into a fabric-like material that targets a specific thermal rate of transfer. A secondary benefit to this approach is that at conduction rates below 0.3 W/(m·K) thermal pain sensation is nearly imperceptible, so cold therapy loses its inherent sting and ice burn and is a more comfortable experience.

Thermal imaging of a similar sized conventional ice pack wrap (water ice gel pack with mesh nylon pocket) in comparison to the übertherm thermal conduction regulating device illustrates the concept. With conventional icing there is irregular mottling and areas of sub-0°C tissue conditions, with a wide range of thermal variance. With the übertherm conduction regulating device there is a near homogeneity of cooling throughout the area of the conduction material (though cooling takes longer to penetrate); no sub-0°C tissue conditions are seen at this rate of thermal conduction.

Fig. 1 – conventional ice pack at 5 minutes
Significant mottling and heterogeneity of cooling, with areas of sub-0°C tissue conditions

Fig. 2 – conventional ice pack at 10 minutes
Significant mottling and heterogeneity of cooling, with continued areas of sub-0°C tissue conditions

Fig. 3 – übertherm thermal device at 10 minutes
Near homogeneous cooling is seen with only small areas of mottling. No sub-0°C tissue conditions are seen.

Fig. 4 – übertherm thermal device at 15 minutes
Near complete homogeneity of cooling without sub-0°C tissue conditions.


Given the potential for both injury and exacerbation of inflammation associated with sub-0°C conditions in the superficial and deeper tissues11, R.I.C.E. therapy should strive to avoid sub-0°C conditions when possible. Cooling without freezing accomplishes the desired result of slowing the influx of proinflammatory cells and reducing blood flow and swelling, and should therefore be considered more ideal than conventional icing.

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