Chapter 94. Cold Injuries

The human capacity for physiologic adaptation to cold is minimal. This deficiency may cause problems, because seasonal changes in the outdoor environment are quite prominent, even in the temperate zones of the world. In this context, skin is important in thermoregulation, and cutaneous blood flow and the resulting skin temperature may vary widely to help preserve the core body temperature.1–3 Physiologic, behavioral, and environmental factors modulate skin responses to cold exposure.

Core body temperature is maintained within a narrow range by thermoregulatory mechanisms that rely largely on control of the cutaneous blood flow. Arteriovenous anastomoses are abundant in acral areas, and they regulate the volume of blood that passes through the skin. When the skin is cooled, there is usually an immediate acute reduction in the amount of blood that flows to the surface. These events alter skin temperature, heat loss, and color. Skin reactivity and the anatomic pattern of blood supply differ in the skin of newborns, adults, and older people. For instance, a reticulate appearance of cooled skin is a common finding in young infants (Fig. 94-1).

The parallel arrangement of large arteries and veins in the limbs allows countercurrent exchange of heat. Vasoconstriction due to cold results in shunting of blood from the superficial to the deep venous system, and heat is transferred from arteries to veins. Thus, the blood going to the acral part of the limbs is precooled, and less heat is lost to the environment. With such thermoregulation, the body can maintain a constant core temperature of approximately 37°C (98.6°F) over a range of external temperatures between 15°C and 54°C (59°F and 129.2°F).

Normally, the skin is to some extent adapted to a cooler environment than the 37°C (98.6°F) of internal organs. Given the presence of many cold-adapted enzymes, the skin may even function more effectively when slightly cooled. In the case of adipose tissue, mild long-term exposure to cooling may lead to progressively better insulation. Habitually cold-exposed skin also develops a more efficient system for shunting blood away from the surface. These adaptive mechanisms are most flexible during the first years of life. Tissues in the aged are less able to develop new shunts.

The effect of swimming in cold water after extreme heating—for example, after using a sauna4—is somewhat comparable to accidental cold water immersion. Well-being depends substantially on the degree of subcutaneous insulation, so that overweight persons, as well as those who are well clothed, can survive prolonged accidental cold-water exposure.5

Viscosity of fluids generally increases as temperature decreases. However, blood is a non-Newtonian fluid that exhibits thixotropy, i.e., it becomes less viscous with increasing flow velocity, independent of temperature. This effect is strongly influenced by hematocrit and by packing of erythrocytes. Macrophages also can block capillaries when they develop pseudopods as a result of reduced flow. The combination of slow flow and leukocyte conformational changes is, in part, a physiologic process that enables these cells to migrate through the endothelial lining.6 Other factors affecting blood viscosity include increased platelet adhesiveness, changes in concentrations of proteins, and the presence of abnormal proteins. Fibrinogen level is particularly important.

Local and systemic thermoregulation is complex. A group of neurons in the hypothalamus responds directly to temperature. When the temperature decreases, the rate of discharges decreases. From this temperature-sensitive area, signals radiate to various other portions of the hypothalamus to control either heat production or heat loss. Stimuli that influence the autonomic nervous system, such as painful stimuli, mental stress, arousal stimuli, and deep breaths, can all produce cutaneous vasoconstriction in warm subjects but vasodilation in cold subjects.7,8

Cold exposure produces an initial massive cutaneous vasoconstriction, which results in a fall in skin temperature. This change serves to maintain core temperature, but at the expense of the skin. Conversely, cold-induced vasodilation represents a protective mechanism to prevent skin necrosis. This physiologic reflex, known as the hunting reaction of Lewis, involves transient cyclic vasodilation caused by the opening of arteriovenous anastomoses.9,10

A chilling effect is produced by applications of dedicated hydrogel pads or cushions previously stored in a refrigerator.11,12 This biothermal procedure is commonly used during laser therapy. It also serves to achieve a sustained removal of heat from the skin and its underlying tissues. It produces discrete skin hemodynamic changes and may relieve pain.

Outdoor work and winter sports are common risk situations for cold damages. A cold environment can be a threat to the skin, leading to a subsequent fall in core body temperature. Many physiologic, behavioral, and environmental factors predispose to the global effects of cold injuries. Marked increases in convective, conductive, or radiant heat loss are responsible for the immediate effects of cold exposure. For instance, touching cold metal objects considerably increases conductive cooling (Fig. 94-2). Other predisposing factors increasing heat loss and/or decreasing heat production and insulation from clothing make people especially susceptible to cold.13

There is ample evidence that the effect of low temperature on skin biology is, in part, a function of environmental humidity, wind speed, and altitude. In this respect, the wind chill index is indicative of the convective heat loss. Wind chill affects the gradients of temperature and water content across the stratum corneum, which result in an imbalance in condition between outer and deeper epidermal layers.14 High altitude, which reduces the oxygen supply to tissues, also contributes to increase the skin damage induced by cold.15

Transepidermal water loss (TEWL) plays a prominent role in evaporative thermal loss. The skin temperature and the relative and absolute environmental humidity are key factors affecting cold injuries. The ambient humidity indicates the mass of water vapor present in a unit volume of the atmosphere. An accurate representation of the amount of moisture in the air as a function of temperature is given by the calculation of the dew point,11,16 which is defined as the temperature of the air at which the gaseous moisture begins to condense, that is, the temperature at which relative humidity reaches 100%.

Poor clothing insulation is a common reason for cold injuries. The insulation is insufficient when clothing is too light, wet, tight, permeable to wind, or inadequate to cover the cold sensitive body parts. Individual factors predisposing to cold injuries are physical injuries, leanness, low physical fitness level, fatigue, dehydration, previous cold injuries, sickness, trauma, poor peripheral circulation, the wearing of tight constrictive clothing, and old age.13 Newborns, the elderly, and individuals with impaired mental faculties remain the most vulnerable. Injury is often increased by alcohol, smoking, and psychotropic drug use.

Severe cold injuries have historically influenced the outcome of battles and wars.17,18 Peacetime military operations also impose risks.19–22 However, cold injuries are becoming more prevalent among the general population.21 Many cases are associated with alcohol consumption, homelessness in urban centers, and car breakdown. Frostbite also prevails among winter sport enthusiasts such as cross-country skiers and backpackers who get lost or trapped in a snowstorm.2,22–26 Accidental exposure to liquefied gas is another cause of severe cold injuries.27

Adaptation to cold protects one from responding inappropriately, and a moderate degree of exposure to cooling might be health promoting by stimulating a responsive and protective vasculature. In contrast, individuals who have experienced severe cold injury may have a profoundly delayed or abolished hunting reaction in the affected limbs.28 They are rendered more susceptible to recurrent cold injury with pain, hyperesthesia, or paresthesia.29 Some of these individuals also have coldness of the skin, which is very persistent and probably related to a functional imbalance in the sympathetic nervous system that results from increased α-adrenergic receptor density or affinity for norepinephrine.30 In addition, altered vascular structure may reduce vasocompliance after cold exposure. There may also be impairment of normal vascular reflexes to various stimuli, including deep inspiration, venous occlusion, neck cooling, and ipsilateral skin cooling.30

Freezing and nonfreezing injuries can be distinguished according to the severity and duration of chilling. However, the damage caused depends on many variables other than the actual temperature. Recognition is generally easy at a clinical level, but awareness of potential uncommon underlying disorders is important. Treatment, both physical and pharmacologic, is aimed at keeping the body warm and maintaining vasodilation.

Frostbite is the consequence of extreme and prolonged freezing conditions. In addition, the whole body may cool down so much that life-threatening hypothermia may ensue. This is an important concern for people who enjoy cold weather sports, particularly in mountains and circumpolar regions. Prompt recognition and treatment are of paramount importance, because many hypothermia victims can recover from very low body temperatures. Treatment in an adequate medical facility can make the difference between full recovery and lifelong problems. Even if the victim appears to be dead from exposure to cold, resuscitative efforts should be started and continued until the proper core body temperature is reached.31

Extreme and often conductive heat loss at a given body site freezes the tissues and results in localized blistering and necrosis (Fig. 94-3). Several cutaneous disorders also occur when the tissue temperature is maintained just above freezing for long periods. These conditions include chilblains, cold urticaria, cold panniculitis, erythrocyanosis, and acrocyanosis, among others. These disorders may be a consequence of impaired blood flow, reduced sensory perception, or a change in the physical properties of the tissues, such as in adipose tissue.

Minor but long-term cold exposure combined with environmental desiccation may have profound effects on the biology of the epidermis, leading, for example, to winter xerosis.32,33 Persistent erythema of the face and the hands is not a rare finding (Fig. 94-4).

Frostbite occurs when tissue freezes after exposure to extremely cold air, liquids, or metals. The clinical effects of accidental injury that leads to the death of tissues are similar to those caused by cryosurgery.34 The components of tissue that may lead to damage when frozen are water, with formation of ice crystals at 0°C (32°F), and lipids such as fat globules or cell membrane constituents.

Contrasting with damaging cryoinjuries, cryopreservation is used to preserve or “to freeze” in vitro most of the biomolecules present in tissues.35 Any metabolic activity is blocked in these circumstances. Cryoscopy is a diagnostic procedure applicable in vivo.36 It relies on an acute but short icing of the stratum corneum in order to disclose some structures exhibiting different capacities of thermal conductivity.

The rate of freezing determines the site of injury at the cellular level.37 Extracellular formation of ice occurs most commonly with slow freezing, whereas fast freezing tends to produce intracellular ice. The formation of ice crystals in the extracellular space alters the osmotic properties of the tissues and disturbs the flow of water and electrolytes across the cell membranes. Thawing may be as damaging as the freezing itself, and repeated freeze and thaw cycles, as may occur in accidental injury, compound the damage, making more water available, which rapidly leads to intracellular flooding. The rewarming rate is also important. In slow rewarming, ice crystals become larger and more destructive. Cells are also exposed to a high concentration of electrolytes for a longer period than with rapid rewarming.

As the body cools, there is a reflex constriction of the arteries and veins in the extremities.31 This results in increased venous pressure, decreased capillary perfusion, and sludging. Cooling also creates a leftward shift in the oxygen dissociation curve, and hemoglobin gives up its oxygen less readily. These two conditions result in hypoxia and damage to the capillaries and surrounding tissue. Oxygen tension is further decreased by thrombus formation in the microvasculature, which results in arteriovenous shunting. Arterial and arteriolar constriction, mediated by sympathetic outflow, initiates and probably maintains circulatory impairment. In addition, segmental vascular necrosis occurs in areas of erythrostasis, which suggests that ultimate damage may depend more on insufficient clearance of toxic substances than on initial vasoconstriction.

Cell types vary in their susceptibility to cold injury. Melanocytes are very sensitive to cold, and irreversible damage may occur at −4°C to −7°C (24.8°F–19.4°F). This sensitivity explains the hypopigmentation that often follows cryotherapy. In addition, it appears that black persons are more susceptible to frostbite than whites. Nerve axons are also easily damaged by cold, and nerve injury may occur with axonal degeneration of large myelinated fibers. Autonomic fibers are also affected, and this may account for the abnormal sweating and cold sensitivity that follow nonfreezing cold injury.38,39 Nerve sheaths are quite resistant to cold, as are bone and cartilage.28 Desolidification of lipids in adipose tissue and disruption of endothelial cells lining blood vessels and lymphatics, with secondary disturbances of permeability and blood flow, are other consequences of severe cold. In the overall assessment, there are marked similarities in the pathologic processes to those seen in thermal burns and in ischemia-perfusion injuries.

Three stages of cooling are recognized. The first is massive vasoconstriction, which causes a rapid fall in skin temperature. In a second step, the hunting reaction follows with a cyclic rise and fall in skin temperature. If cold exposure continues, the third stage of freezing occurs as the skin temperature falls to approach ambient temperature. The events that ensue in freezing and nonfreezing cold injuries are similar.17,40 Consequences of cold injuries and their classification are presented in Tables 94-1 and 94-2, respectively.

Frostbite commonly affects fingers, toes, ears, nose, and cheek.41,42 The clinical presentation of frostbite falls into three categories corresponding to mild frostbite or frostnip, superficial frostbite, and deep frostbite with tissue loss.

Frostnip involves only the skin and causes no irreversible damage. There is a sensation of severe cold progressing to numbness followed by pain. Erythema is usually present on the cheeks, ears, nose, fingers, and toes (Fig. 94-5). There is no edema or bleb formation. Frostnip is the only form of frostbite that can be treated safely in the field with first aid measures.

Superficial frostbite involves the skin and immediately subcutaneous tissues. It includes the previously described signs but with the pain subsiding to feelings of warmth. This is a sign of severe involvement. The skin has a waxy appearance, but deeper tissues remain soft and resilient. Clear blebs form, accompanied by edema and erythema within 24–36 hours after thawing. Lesions may become eroded (Fig. 94-6).

Deep frostbite extends to the deep subcutaneous tissue. The injured skin becomes white or bluish white with a variable degree of anesthesia. Most often the affected skin becomes deceptively pain free, and the discomfort of feeling cold vanishes. The tissue is totally numb, indurated with immobility of joints and extremities. Muscles may be paralyzed. Nerves, large blood vessels, and even bone may be damaged. Large blisters form 1 to 2 days after rewarming, and they can be classified according to depth, as in heat-induced burns (Fig. 94-7). Frostbite blister fluid contains high amounts of prostaglandins, including prostaglandin F2α and thromboxane A2. These mediators may contribute to increased vasoconstriction, platelet aggregation, leukocyte adhesiveness, and ultimately progressive tissue injury. The blister fluid begins to be resorbed within 5 to 10 days, which leads to the formation of hard, black gangrene. Weeks later, a line of demarcation occurs, and the tissues distal to the line undergo autoamputation (Fig. 94-8).

Prevention

Prevention is key to protecting individuals from the effects of cold weather; and frostbite, frostnip, and hypothermia always should be taken seriously. Prognostic factors25,43–46 are listed in Table 94-3. Wearing protective clothing, warm hat, earflaps and scarf together with preventive behavior such as turning bare areas away from the wind are the most important procedures for preventing frostbite. Nonmedicated waterless ointments are traditionally used for protection against facial frostbite, but their benefit is undocumented. The thermal insulation they provide is indeed minimal.41,42 The use of protective emollients seems to cause a false sensation of safety, which leads to an increased risk of frostbite, probably through neglect of other, more efficient protective measures.47,48 In less extreme conditions, however, some specific topical formulations bring beneficial effects.49 The most effective products are those reducing TEWL and perspiration because these biological functions cause emission of body thermal energy and thus cool the skin.

Management

The first consideration in frostbite treatment is to be aware that the victim may be suffering from hypothermia.25,31,50,51 Because of the difficulty in assessing the depth of frostbite injury, conservative waiting after the frostbite episode is often encouraged in an attempt to delineate the extent of tissue loss. Beyond this, the main principles are to avoid trauma, friction, pressure, massaging with snow, and refreezing. Slow rewarming increases tissue damage, and therefore rapid rewarming is the keystone of treatment.20 It should be performed in a water bath no warmer than 40°C–42°C (104°F to 107.6°F) until the most distal parts of the body are flushed. Large amounts of analgesics may be required. The damaged part should be elevated, and blisters should be left intact. Surgical debridement is often best delayed until 1 to 3 months after demarcation. However, triple-phase bone scans, magnetic resonance imaging, and magnetic resonance angiography can be used to predict ultimate tissue loss and to assess the possibility of earlier surgical intervention.40,52,53

There is no uniformly accepted protocol for other measures allegedly beneficial in the treatment of frostbite injury.51 Intra-arterial reserpine and sympathectomy have been used to reverse vasospasm, which may contribute to tissue loss. Their role is controversial, although some patients have benefited from this therapy. To counteract vasoconstriction caused by local release of inflammatory mediators, the use of topical aloe vera, which inhibits thromboxane synthetase, and systemic ibuprofen, which inhibits cyclooxygenase, have been advocated. Oxpentifylline has been presented as an advanced therapy.54 In addition, several adjunctive therapies, including vasodilators, thrombolysis, and hyperbaric oxygen, are sometimes useful.55 Tetanus toxoid should be given in the case of open wounds. Surgery and amputation remain the ultimate strategies to help the victims.56

Sequelae

Sequelae of frostbite include permanent hypersensitivity to cold and, less often, hyperhidrosis.38 Squamous cell carcinoma is a rare outcome, usually occurring on the heel 20–30 years later.57 Epiphyseal plate damage or premature fusion may occur in children. Premature fusion can result in shortened digits, joint deviation, and dystrophic nails. In addition, frostbite arthritis, resembling osteoarthritis, may occur weeks to years later.

Nonfreezing cold injury occurs when tissues are cooled to temperatures between approximately 15°C (59°F) and their freezing point for prolonged periods. This type of injury, which is exacerbated by dampness, has claimed numerous casualties in warfare. Nonfreezing cold injury may be followed by cold sensitivity and hyperhidrosis, which may persist for years.

During World War I, trench foot was identified as a separate entity. Wet conditions at temperatures above freezing and limb dependency due to immobility and constrictive footwear were important pathogenic factors. Three stages were described. Stage I consisted of initial erythema, edema, and tenderness. Stage II followed within 24 hours with paresthesia, marked edema, numbness, and sometimes blisters. Stage III corresponded with progression to a usually superficial gangrene. Immersion foot, similar to trench foot, was described in shipwreck survivors during World War II.

Tropical immersion foot was described during the Pacific campaign in World War II. Occurring after exposure to the warm, wet conditions of jungle warfare, this condition differed from classic trench foot and immersion foot in that it caused less tissue destruction, numbness, and anesthesia and was followed by more rapid complete recovery. The role of temperature in tropical immersion foot is unclear and may not be important.58 As with trench foot and immersion foot, prevention is most important.

Another specific condition known as pulling-boat hands was described, characterized by the presence of erythematous macules and plaques on the dorsum of the hands and fingers of sailors aboard rowboats.59 Small vesicles developed later, accompanied by itching, burning, and tenderness. These individuals were exposed to long periods of high humidity, cool air, and wind, an ideal setting for the development of nonfreezing cold injury. In addition, hours of vigorous rowing daily produced repetitive hand trauma.

Many individuals present with dryness of the skin, particularly on the lower extremities, during wintertime. The hands, forearms, cheeks, lips, and trunk also may be affected. Itching, a dry appearance, chapping, and cracking of the stratum corneum are more or less prominent. The condition is markedly influenced by cold environments, especially in combination with low humidity.38,39 Predisposing factors include atopic dermatitis, ichthyosis, and increasing age. Excessive washing exacerbates winter xerosis. Indeed, irritant dermatitis of the hands worsens in a cold and dry environment.60 Emollients and improvement in the environmental temperature and humidity are helpful in controlling this condition.

Acrocyanosis is a bilateral dusky mottled discoloration of the hands, feet, and sometimes the face. It is persistent and accentuated by cold exposure. When the temperature is very low, the skin may be bright red. Trophic changes and pain do not occur, and pulses are present. This condition must be distinguished from Raynaud phenomenon (see Chapter 170), which is clearly episodic, often segmental, and painful, as well as from obstructive arterial disease (see Chapter 173).

Acrocyanosis is genetically determined and usually starts in adolescence. Chronic vasospasm of small cutaneous arterioles or venules with a secondary dilatation of the capillaries and subpapillary venous plexus has been postulated. Stasis in the papillary loops with aneurysmal dilatation at the tips redistributes blood flow to the subpapillary venous plexus. The blood flow may be compromised by altered erythrocyte flexibility, increased platelet adhesiveness, and other plasma viscosity factors. Cold agglutinins may exacerbate the acrocyanosis manifestations.61,62 The “puffy hand syndrome” is defined by the presence of hand edema superposed on acrocyanosis.63

Tissues are less sclerotic in acrocyanosis than in Raynaud phenomenon. They contain twisted collagen fibrils and large pericytes. In cases developing for the first time late in life, an underlying myeloproliferative disorder should be excluded. Remittent necrotizing acrocyanosis is associated with enhanced susceptibility to cooling and pain, as well as ulceration and gangrene of the fingers. Arteriolar occlusion by thrombi or intimal proliferation may occur. Cold pain should be distinguished from cold allodynia and cold hyperalgesia.

There is no effective treatment for acrocyanosis. Supportive measures to keep the skin warm are helpful.

Erythrocyanosis is a dusky cyanotic discoloration, worse in winter, which occurs over areas with a thick layer of subcutaneous fat (Fig. 94-9). The condition is seen most often on the lower legs and thighs of adolescent girls and middle-aged women. Nodular lesions similar to chilblains may occur and have been described in women with severe erythrocyanosis and paraplegia. Keratosis pilaris, angiokeratomas, and telangiectasia are commonly associated. Spontaneous improvement often occurs after a few years. However, the disease may persist with long-standing edema and fibrosis.

The wearing of warm clothes and weight reduction are important to decrease the insulating effect of the subcutaneous fat, which is responsible for a chronically low skin temperature. The outcome remains unpredictable.

Chilblains, also called pernio or perniosis (Fig. 94-10), are localized inflammatory lesions caused by continued exposure to cold above the freezing point.64,65 Dampness and wind that increase thermal conductivity and convection play a part. Absolute temperature is less important than the cooling of nonadapted tissue. The condition shows a genetic predisposition. It has been described most often in temperate regions, where winters are occasionally cold and damp. Chilblains are seen less often in very cold climates, where well-heated houses and warm clothing are available. Both acrocyanosis and chilblains appear to be more common in children, women, and persons with low body mass index. Spontaneous remission is common when spring arrives, and relapse is frequent during the following winters. However, chilblains do not always occur at the time of maximum cold.

Chilblains develop acutely as single or multiple, burning, erythematous, or purplish swellings (see Fig. 94–10A and C). Patients may complain of itching, burning, or pain. In severe cases, blisters (see Fig. 94-10B), pustules, and ulceration may occur. Characteristic locations include the proximal fingers and toes, plantar surfaces of the toes, heels, nose, and ears, but other sites like the calves and thighs can be affected66,67 (see Fig. 94-10C). Lesions usually resolve in 1 to 3 weeks but may become chronic in elderly people with venous stasis. Tight garments such as gloves, stockings, and shoes are especially to be avoided in cases in which there is also peripheral vascular disease. A papular form of chilblains resembles erythema multiforme and occurs at all times of the year, usually in crops on the sides of the fingers,68 often superimposed on a background of acrocyanosis.

A peculiar clinical presentation may occur in young women riding horses for several hours daily during winter.69,70 Indurated red-to-violet tender plaques develop on the lateral calves and thighs (see Fig. 94-10C). The condition is quite similar to the nodular perniotic lesions described in adolescent girls with erythrocyanosis. For prophylaxis, experienced riders usually wear baggy breeches that provide insulation and are not tight enough to compromise the circulation.

Perniotic lesions have been described in association with myeloproliferative disorders,71 probably as a consequence of blood flow changes, presence of cold agglutinins, and altered inflammatory response on cooling.

Idiopathic perniosis is characterized histologically by edema of the papillary dermis and by the presence of superficial and deep perivascular lymphocytic infiltrates. Necrotic keratinocytes and lymphocytic vasculitis also have been reported. Thickening of blood vessel walls with intimal proliferation may lead to obliteration of the vascular lumen.72–74

Chilblain lupus is a distinct disease and is similar to discoid lupus erythematosus.75,76 Lupus pernio is a variant of sarcoidosis (see Chapter 152) and is unrelated to cold injuries.

The unfamiliarity of physicians with chilblains sometimes gives rise to unnecessary hospital admissions with expensive laboratory and radiologic evaluations and, at times, hazardous therapy. The most important point in management is prophylaxis through the use of adequate, loose, insulating clothing and appropriate warm housing and workplace. Maintaining the blood circulation by avoiding immobility is also helpful. A short course of ultraviolet light therapy at the beginning of winter was a recommendation but has been challenged.77 Once chilblains occur, treatment is symptomatic with rest, warmth, and topical antipruritics. Calcium channel-inhibiting drugs may be effective in the treatment of severe recurrent perniosis,78 although they may cause headache and flushing that are troubling to some patients. In cases of crippling severity, thyrocalcitonin and hemodilution may be helpful.

Acquired cold urticaria is a form of physical urticaria (Fig. 94-11). Lesions occur at sites of localized cooling, usually when the area is rewarmed. The disease is recognized by wheal and flare-type reactions and/or angioedema. The condition may be idiopathic or associated with some serologic abnormality.79–83 It accounts for approximately 2% of cases of urticaria (see Chapter 38).

Most cases fall into the group of essential cold urticaria. They can be subdivided into a rare familial type and an acquired form. Immunoglobulin E and, more rarely, immunoglobulin M have been implicated in the pathogenesis. The antigen is likely a normal metabolite produced on exposure to cold. Histamine is one of the most important mediators, but leukotrienes, platelet-activating factor, and others have been incriminated. In this disease, exposure to cold causes prolonged edematous papules and plaques, often with headache, fever, arthralgia, and leukocytosis. Swelling of the oral mucosa and esophagus may occur on ingestion of cold liquids. A rather distinctive combination of cold urticaria and dermographism or cholinergic urticaria is not uncommon. Alarming signs resembling those of histamine shock may lead to loss of consciousness. Death while swimming in cold water has been reported.

Familial cold urticaria is a rare autosomal dominant condition with onset at an early age.84,85 A mutation in the gene responsible for the cold-induced autoinflammatory syndrome-1 (CIAS1) has been identified.85 Urticaria develops when the patient is exposed to generalized cooling, particularly chilling wind, rather than local cold application. The delayed type of familial cold urticaria is characterized by localized angioedema developing 9 to 18 hours after cold exposure.

Cold urticaria may occur in 3%–4% of patients with cryoglobulinemia, and it also may be associated with cold agglutinins, cryofibrinogens, and cold hemolysins. Cold urticaria has been reported in cases of infectious mononucleosis in association with either cryoglobulins or cold agglutinins, but such occurrences are rare. Cold urticaria may also be a sign of the Muckle–Wells syndrome that associates urticaria, deafness and amyloidosis.86 In this rare genetic disorder recurrent bouts of urticaria, fever, chills and malaise may occur from birth and persist throughout life. Helicobacter pylori has been suggested as a causative agent in some cases of acquired cold urticaria.87

Diagnosis of cold urticaria is confirmed by a cold challenge induced by an ice cube wrapped in a plastic bag placed on the skin of the forearm for periods varying from 30 seconds to 10 minutes (see Fig. 94-11). Wheals form on rewarming. Sometimes water at 7°C (44.6°F) is more effective, presumably because it causes less severe vasoconstriction. Peltier effect-based temperature challenge appears to be an improved method for diagnosis.88 The Peltier effect relies on using two different heat-transferring metals to generate a precise skin surface temperature, sufficiently cold, to induce lesions. The temperature is regulated by a microprocessor control unit monitoring the actual temperature at the test site.

Cold erythema seems to be a related disorder with erythema and pain but without urticaria. Familial polymorphous cold eruption is a rare autosomal dominant disease characterized by childhood onset of nonpruritic, erythematous patches often accompanied by influenza-like symptoms and leukocytosis after generalized exposure to cold. Results of the ice cube test are negative. The pathogenesis remains unknown. The disease frequently has been referred to as familial cold urticaria, although the skin lesions are not urticarial.89

Avoiding cold wind exposure and swimming in cold water are important preventive measures. Antihistamines reduce clinical signs and symptoms. Desensitization to cold is possible by immersing one arm into water at 15°C (59°F) for 5 minutes daily.

Cold injuries may affect the subcutaneous tissue in different ways. The freezing injury in deep frostbite results in tissue gangrene. Nonfreezing injuries also can alter the hypodermis. Among them, cold panniculitis is more common in children than in adults. It affects the cheeks and legs most commonly. Tender erythematous subcutaneous nodules appear 1 to 3 days after exposure and subside spontaneously within 2 to 3 weeks. Ice cube challenge to the child's skin for 10 minutes results in the development of an erythematous plaque 12 to 18 hours later.

A perivascular mixed infiltrate with neutrophils, lymphocytes, and histiocytes is present at the dermal–subcutaneous junction after 24 hours, followed by a well-developed panniculitis at 48 to 72 hours. Some adipocytes are necrotic and rupture to form cystic spaces. The reaction subsides completely in 2 weeks. Infants have a higher content of saturated fatty acids in adipose tissue than do adults, and this may result in solidification at higher (less cold) temperatures.90,91 Cold panniculitis should be distinguished from other related disorders, including erythrocyanosis with nodules, sclerema neonatorum, and subcutaneous fat necrosis of the newborn.

(See Chapters 70 and 107)

Sclerema neonatorum and subcutaneous fat necrosis of the newborn are distinct disorders involving the subcutaneous fat of the newborn. As noted in the prior paragraph, infant fat differs from adult fat in that it has a higher saturated–unsaturated fatty acid ratio, which results in solidification at a higher temperature. Prematurity and immaturity of enzyme systems may result in a relative inability to desaturate fatty acids, which alters the ratio further. Sepsis, dehydration, chilling, infection, and other stresses also may inhibit the enzyme system. Thus, infants in general, and premature or otherwise compromised newborns in particular, are susceptible to such disorders.

Sclerema neonatorum is a rare disorder characterized by diffuse, rapidly spreading hardening of the skin and subcutaneous tissue in infants.92 It starts on the buttocks and trunk, usually in the first week of life. Palms, soles, and scrotum are spared. Fifty percent of affected infants are premature. They have difficulty feeding and are lethargic, and many are otherwise debilitated. Septicemia is frequent, and the prognosis is poor. Cold exposure does not seem to be important in the etiology of sclerema neonatorum; however, similar clinical findings have been seen in cases of primary cold injury.93 Histologically, the subcutaneous layer is greatly thickened by enlarged fat cells and wide, fibrous bands. There is no fat necrosis, and many of the fat cells contain fine needle-like clefts.94

Treatment of sclerema neonatorum involves correcting dehydration and electrolyte imbalance and treating septicemia if present. The value of systemic glucocorticoids is controversial. Successful treatment with exchange transfusions has been reported.95

Subcutaneous fat necrosis of the newborn is characterized by discrete red to violaceous mobile plaques and nodules that usually appear within a few days of birth. The back, thighs, and cheeks are most commonly affected. Fat necrosis and crystallization are the hallmarks of the disease. There may be a granulomatous inflammatory response with foci of calcification. In most cases, the condition is benign and self-limited, although it has been associated with hypercalcemia and death.96

As in sclerema neonatorum, there is no clear etiologic relationship to cold, and the cause is likely multifactorial. It has been postulated that an underlying defect in fat composition, poor nutrition, and various physical stresses such as hypothermia may be important.

Erythromelalgia or erythermalgia is a rare chronic cutaneous disorder characterized by erythema, burning discomfort, and warmth of the extremities.97,98 Primary erythromelalgia is an autosomal dominant neuropathic disorder involving a mutation in a voltage-gated sodium channel subunit.99–106 Vasoconstriction apparently precedes reactive hyperemia, similar to that seen in Raynaud phenomenon. An early-onset type and an adult-onset type have been recognized. When the extremity is lowered or heat is applied, the pain is intensified. The application of cold or elevation of the extremity has the opposite effect of decreasing the pain. Idiopathic erythromelalgia may involve increased thermoregulatory arteriovenous shunt flow. Secondary erythromelalgia is associated commonly with myeloproliferative syndrome-related thrombocythemia and is mostly evident in the adult-onset type.

Treatment for adults with erythromelalgia includes a single daily dose of acetylsalicylic acid (aspirin), but children who have no associated underlying disorder obtain little to no relief from the drug. Other drugs including mexiletine107 and venlafaxine108 may also help. Pain may be decreased by topical amitriptyline combined with ketamine.109 Lidocaine in patches110 or administered intravenously in combination with oral mexiletine111 may also alleviate pain. Sympathectomy in the upper extremities is another option for treating refractory primary erythromelalgia.112

(See Chapter 170)

(See Chapter 169)

(See Chapter 173)