Chapter 7 Nonfreezing Cold-Induced Injuries
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Nonfreezing cold-induced injury (NFCI) is a clinical syndrome that results from damage caused to tissues exposed to cold temperatures at or above the freezing point of water (0° to 15° C [32° to 59° F]). NFCI does not involve tissue freezing, which distinguishes it both clinically and pathologically from frostbite.36 The earliest descriptions of this syndrome had their origins in the military. Baron Dominique Jean Larrey, Napoleon’s chief surgeon, used the word congelation to describe the nonfreezing injuries together with frostbite casualties that occurred during the 1812 assault on Russia.92 Historically, infantry regiments have been decimated by cold and wet conditions, and many medical advances in understanding the pathophysiology and clinical course of NFCI have occurred after wars.2,35 However, it has been observed that the continuity of research tends to lag during the periods between major military campaigns.98 Developments in prevention of cold injury have flourished as new clothing and footwear have been designed, but little progress has been made in the treatment of NFCI.
There is a rise in the number of people pursuing recreational activities in harsh environments, and as a consequence, civilian NFCI is becoming more prevalent. However, because many physicians are unfamiliar with NFCI, it may go undiagnosed during assessment of the cold-exposed victim.98 This results in unnecessary hospital admissions and potentially harmful and expensive therapy.41 Proper education and awareness of the hazards innate to the cold environment should mean that NFCI is preventable in most circumstances.
Epidemiology
Individuals suffering cold and wet extremities for extended periods are at risk for NCFI. During the 1800s, NFCI was observed more frequently when the temperature hovered around the freezing point—when the ground was muddy rather than frozen.43,91 Standing or sitting for long periods, wearing constrictive footwear, malnutrition, fatigue, or the blunt trauma of marching on cold, wet feet all added to the severity of injury.92 Original animal studies that modeled NFCI demonstrated that cold temperatures near the freezing point were more likely to cause injury when the extremities were wet than when they were dry.10,91 Ambient temperature and wind speed can both influence cooling.32,114
With “shelter limb” (dependency without cold) and “paddy foot” (wet but not cold), one observes an injury that has no apparent distinguishing differential feature from NFCI. This suggests that neither cold nor wet is a prerequisite to developing the injury. It appears that NFCI is a reperfusion injury that develops after a sustained period of peripheral vasoconstriction.98
Military
In combat settings, there is rarely the time, equipment, or opportunity to apply appropriate remedies to NFCI. In the 1854 Crimean War, cold injury was documented more often among “the men in the trenches [who] were so restricted in their movements.… Frequently this position happened to be the bottom of a trench knee-deep in mud and water or half-filled with snow.”91 In November 1944, during World War II, American forces sustained 11,000 cases of trench foot.110 Evaluation of possible risk factors for cold injury during the 1982 war in the Falkland Islands has been published. A year after exposure, there were no cases of cryoglobulinemia or hematologic evidence to suggest that any of the men who developed cold injury had abnormal circulating proteins, plasma hyperviscosity, or indicators of alcohol abuse.20 In the 1990s, both the U.S. Army and the Israel Defense Forces recorded that the majority of nonfreezing cold injuries occurred during routine training exercises, rather than during combat operations.26,68,73
Ethnicity
Historically, the first reports of increased susceptibility in certain ethnic groups (blacks) to cold-weather injury came from the American Civil War.87 It was also noted that there was an increased incidence of cold injuries among blacks in the cold winter conflict in the Ardennes in 1944 during World War II.110 A major retrospective study looking at 2143 U.S. Army cold-weather injury hospital admissions between 1980 and 1999 found that the injury rates for men and women were 13.9 and 13.3 per 100,000 soldiers, respectively.26 Increased rank and experience were associated with a decrease in cold-weather injuries. There were 3.3 times more blacks hospitalized than whites, (95% confidence interval [CI], 3.1-3.7), and infantry and gun crews appeared to be at greater risk. There was a marked reduction in the number of soldiers admitted to the hospital between 1980 and 1999, from greater than 30 cases per 100,000 soldier years to almost zero.
Young male African Caribbeans in the British Army have been found to have a 30 times greater chance of developing peripheral cold injury and are more severely affected than are their white counterparts following similar climatic exposure, using similar clothing and equipment. Pacific Islanders carry a 2.6 times increased risk, whereas being a Gurkha appears to be protective.15 Peripheral vascular responses to a local cold stress were studied in four groups of Indians: South Indians, North Indians, Gurkhas, and high-altitude natives of 3,500 meters (11,483 feet). The heat output and cold-induced vasodilation (CIVD) were highest in high-altitude natives, with the lowest observed in South Indians.67
Prevalence
In most North Atlantic Treaty Organization (NATO) countries, prevalence of NFCI injuries appears to be static or decreasing among military personnel. However, in the British military, there appears to be a marked increase in the incidence of reported cold-weather injury. Over a 4-year period, the reported rate increased from 9 per 1000 to 30 per 1000 recruits, with the majority of cases (90%) originating during field-based training. Independent factor analysis demonstrated that African Caribbeans were 13.2 (95% CI, 9.5-18.4, probability [p] <0.01) times more likely to report cold injury and 27.3 (95% CI, 16.3-45.9, p <0.01) times more likely to be medically discharged than were whites.113 The rise in NFCI in the military of the United Kingdom (UK) may be caused by increased exposure, lower threshold to diagnose the condition, increased awareness, or recruiting of a different and more sensitive population. Alternatively, the rise may be caused by a type I statistical error (poor specificity of the tests used to diagnose NFCI or excessive credulity) or a type II error (poor sensitivity of the tests used to diagnose NFCI). Perhaps other countries are failing to diagnose and report the condition.52
Civilian
The environmental conditions that can produce NFCI in military settings are also found in the context of wilderness medicine. Outdoor recreation may lead to cold, dehydrated, exhausted, and wet hikers exposed to the elements for an extended period. These individuals may be unwilling or unable to take the time and effort to care for their wet boots and socks, and they may be unaware of the risks inherent in the situation. Other civilian populations at risk for NFCI include the homeless,116 older adults,83 and alcoholics.98
Personal Administration
Proper protective equipment and appropriate use are important factors reducing the incidence of NFCI. Factors affecting the incidence of frostbite are closely related to those affecting NFCI. A surprisingly high incidence of frostbite has been reported in mountaineers. In one study, the mean incidence was 366 per 1000 population per year. Mild (grade 1) injury (83.0%) and hand (26.4%) and foot (24.1%) involvement were most common. There was a significant relation between lack of proper equipment (odds ratio 14.3) or guide (p <0.001) and the injury. Inappropriate clothing, lack or incorrect use of equipment, and lack of knowledge of how to deal with cold and severe weather were claimed to be the main reasons for the injury.47
Cold injury is uncommon in Antarctica. Despite this, it warrants a continued high profile, because under most circumstances, it may be regarded as an entirely preventable occurrence.16 It has been suggested that prolonged heavy load carriage during a 109-day Arctic expedition may have impaired blood flow or nerve conduction in the hands and inhibited cold acclimatization. However, a different response was observed in the feet, where there was improvement in cold acclimatization despite development of moderate trench foot.77
Civilian Case Reports
Laden and colleagues64 reported cold injury to a diver’s hand after a 90-minute dive in 6° C (42.8° F) water. With the advent of “technical diving,” characterized by going deeper for longer (often in cold water), and adventure tourism, it was suggested that this extremely painful condition was likely to increase in prevalence.
Older adult patients commonly present to the hospital following their collapse and a period of distressing immobilization on the floor. A case of bilateral trench foot in an older adult immobile patient has been reported.112
Skin—A Thermoregulatory Organ
Thermoregulation is a major function of skin in humans, and it is achieved by large fluxes in cutaneous blood flow.65 The metabolic requirements of skin are fixed and relatively modest; the observed large fluctuations in cutaneous blood flow are primarily determined by the individual’s thermoregulatory needs. Arteriovenous anastomoses (AVAs) abound in the extremities. The AVAs are coiled muscular-walled vessels approximately 35 µm in diameter and have little basal tone. They are under dual control. First, there is central hypothalamic control via the sympathetic nervous system. Second, there is direct local control allowing dilation under warm conditions and constriction with a cold stimulus. The two effects may be additive. Cutaneous vessels are controlled by sympathetic adrenergic vasoconstrictor fibers, and vascular smooth muscles have both α- and β-receptors. When core temperature exceeds 37.5° C (99.5° F), the hypothalamus reduces vasoconstrictor drive to the AVAs and vasodilation occurs. As a result, a low-resistance shunt in the dermal venous plexus opens, which in turn increases local heat loss. Under cold conditions there is an increase in sympathetic tone, resulting in local arteriovenous vasoconstriction and reduction in cutaneous blood flow.
Cold-Induced Vasodilation
When the hand or foot is cooled to 15° C (59° F), maximal vasoconstriction and minimal blood flow occur. If cooling continues to 10° C (50° F), vasoconstriction is interrupted by periods of vasodilation and an associated increase in blood and heat flow. This CIVD, or “hunting response,” occurs in 5- to 10-minute cycles to provide some protection from the cold. Prolonged repeated exposure to cold increases CIVD and offers some degree of acclimatization. Inuit, Sami, and Nordic fishermen have a very strong CIVD response and very short intervals between dilations, which may contribute to maintenance of hand function in the cold environment.44 CIVD responses are more pronounced when the body core and skin temperatures are warm (hyperthermic state) and suppressed when they are cold (hypothermic state), when compared with normothermia.22,23,78 Cheung and Mekjavic17 investigated whether CIVD responses of one finger can predict the responses of other fingers and also whether the CIVD of fingers could predict CIVD responses of the feet and toes. They found that CIVD is highly variable across the fingers and is not a generalizable response across either digits or limbs. Paradoxical CIVD will normally prevent tissue damage, but in conditions such as Raynaud’s disease, the vessels of the toes and fingers exhibit an exaggerated and sustained vasoconstriction response, resulting in blanching, numbness, and paresthesias and in severe cases tissue loss.
Subjects with a weak CIVD to experimental cold-water immersion of the fingers in a laboratory setting have been shown to have a higher risk for local cold injuries when exposed to cold in real life.24 There is a strong relationship between the mean temperature of the fingers during cold-water immersion and toes during cold-air exposure (correlation coefficient for bivariate analysis [r] = 0.83, p <0.01), showing that a weak CIVD response in the hand correlates with a weak response in the foot.105 Felicijan and colleagues33 found evidence for significant enhancement of the CIVD response after brief high-altitude acclimatization and that these changes were especially prominent in the feet of Alpinists when compared with controls.
Temperatures of the extremities can drop surprisingly quickly in the field. Toe temperatures of 10 subjects were monitored in the field in Arctic Norway (minimum air temperature −27° C [−16.6° F]). The lowest skin temperature recorded was 1.9° C (35.4° F). The mean estimated time for toe temperature to cool from 25° C (77° F) to 5° C (41° F) was 109 minutes (standard deviation [SD], 10.2) at an ambient temperature of −21° C (−5.8° F). One subject experienced a toe temperature below 5° C (41° F) for 2.9 hours during a 27-hour period. Surprisingly, none of the subjects demonstrated clinical signs of cold injury, but this does not mean that this exposure was without risk.101
The cutaneous microcirculation of skin was assessed in patients with sequelae from local cold injuries. All patients reported cold intolerance 3 to 4 years after the primary cold injury (sustained during military service).4 The transcutaneous oxygen tension was decreased, but oxygen reappearance time, oxygen recovery index, postocclusive reactive hyperemia, and venoarterial reflex were normal. No capillary nailfold abnormalities were found. Local cold injuries appear to cause disturbances in the CIVD, impaired cold tolerance, and increase the risk for future cold injuries. There is evidence to suggest disturbances of reflex mechanisms mediated by the central nervous system. Neurophysiologic factors seem more important than ischemic mechanisms in the pathophysiology of late sequelae with peripheral cold-weather injuries.
Trench Foot (Immersion Foot)
Pathophysiology
Continuous exposure to a cold, wet environment causes skin breakdown, directly cools nerves in the area of exposure, and causes prolonged vasoconstriction. NFCI is primarily caused by prolonged vasoconstriction, which in turn causes direct injury to the vessels (and endothelium) that supply blood to nerves, fat, and muscle cells.49,72,98 Pain, fear, constrictive footwear, and immobility interact in maintaining vasoconstriction through a heightened sympathetic nervous system response or by mechanically limiting blood flow (Figure 7-1). Nerve cooling has been suggested as a contributing factor in the development of NFCI. Large myelinated fibers (C fibers) are most susceptible to prolonged cold exposure.53,61,62,88 In severe nonfreezing cold injury, there is characteristic peripheral nerve damage and tissue necrosis.54 Clinical sensory tests indicate damage to both large- and small-diameter nerves. The prolonged cold injury affects blood vessels serving these large myelinated fibers, with subsequent ischemia causing decreased oxygen to the nerve, resulting in the appearance of a primary nervous system injury58,59 (Figures 7-2 to 7-5).
Vasoconstriction is mediated by presynaptic vesicle release of norepinephrine and neuropeptide Y from sympathetic nerve fibers that interact postsynaptically on smooth muscle at α2C6,18 and Y195 receptors. Recent work100 demonstrated that cold-induced vasoconstriction is mediated by Rho kinase. The prolonged decrease in blood flow caused by vasoconstriction causes direct injury to capillary endothelium. Studies indicate that the endothelial lining separates from underlying cells, leaving “gaps.”31 Leukocytes and platelets fill in these gaps and accumulate to further decrease capillary blood flow, leading to ischemia and eventual tissue hypoxia (Figure 7-6, online). The degree and duration of cold exposure determine severity of the injury.
Animal models have been developed to understand the underlying pathophysiology of NFCI. Thomas and co-workers99 developed a rat model of NFCI by immersing the tail in 1° C (33.8° F) water for 6 to 9 hours and characterized the loss of CIVD and a prolonged decrease in tail blood flow followed by an increase in blood flow above baseline. This pattern is similar to that clinically observed in humans during the prehyperemic phase followed by the hyperemic phase. In rats, absence of CIVD with prolonged cold exposure is similar to this prominent and consistent finding of NFCI in humans.
Stephens and associates95 used the rat tail model in an attempt to elucidate possible mechanisms that cause vascular endothelial damage. Their preliminary data suggest that acute cold-water exposure causes loss of nitric oxide–dependent endothelial function and possibly a change in smooth muscle contractility. Using a rabbit hind limb model, Irwin53 demonstrated that cold-water immersion damaged large myelinated fibers while sparing small myelinated and unmyelinated fibers.
Nonfreezing cold injuries affect many different types of tissue. Pathologic examination of specimens displays a variety of lesions in skin, muscle, nerves, and bone.8,9,38 Muscles exhibit separation of cells and damage to muscle fibers, described as acidophilic and hyalinized (Zenker’s hyaline degeneration). The myoplasm within muscle loses its cross striation, and the healing muscle appears to undergo fibrous tissue replacement.
One of the major pathologic processes in cold injury is progressive microvascular thrombosis following reperfusion of the ischemic limb, with cold-damaged endothelial cells playing a central role in the outcome of these cold-injured tissues.71 Reperfusion of previously ischemic tissues causes free radical formation, leading to further endothelial damage and subsequent edema. With restoration of blood flow, there is reintroduction of oxygen species within cells that further damages cellular proteins, DNA, and the plasma membrane. Free radical species may also act indirectly in redox signaling to initiate apoptosis. Leukocytes may accumulate in small capillaries, obstructing them and leading to more ischemia.59
In an in vivo rabbit hind limb model subjected to 16 hours of cold immersion (1° to 2° C [33.8° to 35.6° F]), there was reduction in the number of myelinated nerve fibers of all sizes, most marked in large-diameter fibers, a feature consistent with ischemic neuropathy and reperfusion injury.54 Unmyelinated fibers showed only minor damage. The resulting evidence has suggested that both of these mechanisms may contribute to the nerve injury. There is further extensive supporting evidence that established NFCI is associated with histologic and/or clinical evidence of nerve damage.27,30,59,76
Das and colleagues25 demonstrated that quinacrine, an antioxidant, decreased damage to cell membrane phospholipids upon rewarming and reperfusion, although more recent studies97 have shown no benefit from antioxidant use. Most importantly, both these studies used models that assumed that cold-induced nerve injury, rather than capillary or endothelial damage, is the primary cause of NFCI.
Clinical Presentation
Trench foot and immersion foot are clinically and pathologically indistinguishable but have different etiologies. The term trench foot originated during the trench warfare of World War I,110 when soldiers wore wet boots and socks for prolonged periods.5 Immersion foot was first medically documented during World War II among shipwreck survivors whose feet had been continuously immersed in cold water.21 Both injuries occur when tissue is exposed to cold and wet conditions at temperatures ranging from 0° to 15° C (32° to 59° F). Colder temperatures decrease the time required to induce NFCI.10,92 Severe nerve damage from immersion foot has been seen after exposure periods of 14 to 22 hours.103,104 Immersion foot injury may extend proximally and involve the knees, thighs, and buttocks, depending on the depth of immersion.111 Clinically, NFCI is insidious in onset, with progression from initial exposure through three distinctive phases (prehyperemic, hyperemic, posthyperemic). These phases have variable time courses and may overlap.
Prehyperemic Phase
During the prehyperemic phase, the affected limb, both during and immediately after cold exposure, appears blanched, yellowish white, or mottled but seldom blistered (Figure 7-7).104 Whayne and DeBakey110 state that the degree of edema during this prehyperemic stage is less severe if the feet are intermittently rewarmed during the course of exposure. Whereas muscle cramps are common, pain is rare.43,92 The single most important diagnostic criterion is loss of a sensory modality, most typically complete local anesthesia, which is distinct from premonitory feelings of extreme cold in the affected periphery, almost invariably in the feet although hands can also be affected. With further exposure, the cold sensation leads to complete anesthesia with loss of proprioception, resulting in numbness and gait disturbances. This sensation has been described as “walking on air” or “walking on cotton wool.”104 Capillary refill is sluggish, and pedal arterial pulses are usually absent, except through Doppler examination.70 Intense vasoconstriction is the predominant feature of this stage.46
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