The Triaging and Treatment of Cold-Induced Injuries
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Background: In Central Europe, cold-induced injuries are much less common than burns. In a burn center in western Germany, the mean ratio of these two types of injury over the past 10 years was 1 to 35. Because cold-induced injuries are so rare, physicians often do not know how to deal with them.
Methods: This article is based on a review of publications (up to December 2014) retrieved by a selective search in PubMed using the terms “freezing,” “frostbite injury,” “non-freezing cold injury,” and “frostbite review,” as well as on the authors’ clinical experience.
Results: Freezing and cold-induced trauma are part of the treatment spectrum in burn centers. The treatment of cold-induced injuries is not standardized and is based largely on case reports and observations of use. A distinction is drawn between non-freezing injuries, in which there is a slow temperature drop in tissue without freezing, and freezing injuries in which ice crystals form in tissue. In all cases of cold-induced injury, the patient should be slowly warmed to 22°–27°C to prevent reperfusion injury. Freezing injuries are treated with warming of the body’s core temperature and with the bathing of the affected body parts in warm water with added antiseptic agents. Any large or open vesicles that are already apparent should be debrided. To inhibit prostaglandin-mediated thrombosis, ibuprofen is given (12 mg/kg body weight b.i.d.).
Conclusion: The treatment of cold-induced injuries is based on their type, severity, and timing. The recommendations above are grade C recommendations. The current approach to reperfusion has yielded promising initial results and should be further investigated in prospective studies.
Patients with frostbite or other cold-induced trauma are treated in burn centers. However, despite the similarity in clinical findings, the differences in etiology and pathophysiology between cold-induced injuries and burns affect the treatment and prognosis. Both types of injury lead to damage or even loss of the skin and the cutaneous and subcutaneous capillary system with planar wounds. Depending on the site and severity of cold-induced injury, the spectrum of treatment extends from conservative management to complex surgical reconstruction. The outcome may be anywhere between full recovery with no consequences and death from the associated hypothermia or infections. The resulting extensive wounds require elaborate sterile treatment. Centers for treatment of severe burns offer the necessary infrastructure and experience. The environment of the patient's room can be adjusted as required, and there are similarities in the surgical treatment of burns and cold-induced injuries, from superficial removal of dead skin to large-scale amputation.
Cold-induced injuries are divided into frostbite and non-freezing cold injuries (NFCI) (Table 1).
Owing to the relatively low prevalence in Central Europe (1 out of every 35 patients in our collective), there are far fewer publications on frostbite and its treatment than on burns; the level of evidence is low. Only a small number of prospective randomized clinical trials have been carried out, with low numbers of cases. The literature consists largely of case reports and observational studies (Table 2).
We conducted a selective survey of the literature in PubMed up to December 2014, using the search terms “frostbite injury”, “non-freezing cold injury”, and “frostbite review”. We also drew on our own clinical experience.
The tissue damage in frostbite is caused by formation of ice crystals (1). The severity of injury ranges from circumscribed superficial cutaneous lesions to necrosis of all layers of the skin (2) (Figures 1 and 2, Table 3). As well as the above-mentioned similarities between frostbite and burns, there are also distinct differences. For example, angiogenesis begins much sooner in frostbite injuries, and inflammation is less accentuated than in burns but persists much longer (3). In contrast to burn injuries, frostbite does not completely destroy the extracellular matrix. Extracellular ice crystals damage the cell membrane, dehydration of the cells ensues, and the result is hyperosmolar cell death (4). Migrating fibroblasts replace the dead cells (3).
Exposed parts of the body with a thin covering of skin and soft tissues, such as the fingers, toes, ears, and nose, are particularly at risk of frostbite.
In contrast to classic frostbite, NFCI are characterized by a slow decrease in tissue temperature without direct freezing (5, 6). The organism seeks to maintain local perfusion and the systemic temperature by means of a cascade of processes: First come shivering and peripheral vasoconstriction; this increases the susceptibility of the tissue to the low temperature. The greatest vasoconstriction is found at a tissue temperature of 15 °C (5). If the temperature falls further to 10 °C or exposure to cold continues, the vasoconstriction is repeatedly interrupted by phases of vasodilation (5). The extent of this vasodilation, known as “hunting response,” depends on the body temperature and is reduced in hypothermia (7–9). This represents an attempt by the organism to prevent complete loss of perfusion in the affected area. The result is a decrease in core temperature (2). If the cold exposure persists, endothelial damage ensues with formation of microthrombi and ultimately occlusion of the capillary bed resulting in ischemia, degranulation of mast cells with excretion of histamine and subsequent edema (Figure 1) (2, 10–16). Warming is followed by ischemia–reperfusion damage (2). Prostaglandin F 2α (PGF2α) and thromboxane A2 (TXA2) lead to thrombocyte aggregation and thus extension of the area of ischemia (2).
The principal factor in the development of NFCI is thought to be the persisting vasoconstriction (5). If the nerves are cooled to under 10 °C, they suffer relevant damage (17). Large myelinated fibers are more susceptible than small and unmyelinated fibers (17, e1–e5). The precise pathophysiological foundations of the neural damage have not yet been uncovered (18, 19, e1, e6). Hypothermia of the nerves is held to be responsible for the ensuing damage (Table 4).
A rough division of cold-induced injuries into superficial and deep injuries, on the basis of the clinical appearance, has become established in clinical routine and in the preclinical setting (Table 2) (20). If the injury is accompanied by formation of blood blisters or full-thickness necrosis, it is classified as deep (Figures 2 and 3).
In the German-speaking countries, however, cold-induced injuries are classically divided into four categories, in analogy to burns (Table 3).
The appropriate treatment for frostbite depends on the severity of injury and the time point (Table 3, Figure 3, Box).
In the prehospital phase, the first priority is to rule out severe accompanying injuries, particularly after falls or road traffic accidents. Next, the patient should be transferred to a protected environment in order to minimize the likelihood of further exposure to cold (21). Wet clothing must be removed immediately. The administration of aspirin (75 mg) to inhibit thrombocyte aggregation is controversial because of the non-selective inhibition of prostaglandin synthesis. Ibuprofen (12 mg/kg body weight [BW] b.i.d.) should be given because of its anti-prostaglandin and analgetic effects (evidence level 3) (2), with the principal aim of inhibiting the thrombogenic action of PGF2α and TXA2. Direct application of heat and warming of the affected part of the body by rubbing are not indicated. The affected area should not be warmed until renewed exposure to cold can be excluded, because alternating freezing and thawing processes can lead to severe thrombosis and ischemia.
In the hospital phase of treatment, the priority is increasing the patient's body temperature. Once this exceeds 34 °C, local treatment of the frostbite can begin (2).
In the case of NFCI, rapid warming of the involved parts is contraindicated because it usually leads to reperfusion damage. The affected blood vessels are not in the position to supply the injured cells with the required nutrients and remove noxious metabolites (5). In contrast to hypothermia, in which the priority is to increase the body temperature, patients with NFCI should be treated by slow warming of the affected area (5). An air current of 22 to 27 °C is recommended for this purpose (10). In the late phase of NFCI, administration of amitriptyline is indicated for analgesia, beginning with a dose of 10 to 25 mg at night and increasing to a maximum of 100 mg as required in the course of treatment (5).
In the event of acute frostbite, the affected extremity should be bathed for 15 to 60 min in water at a temperature of 37 to 39 °C containing an antibacterial agent. An animal experiment showed that rapid warming was clinically superior to slow warming in rats and dogs (evidence level 2b) (22). In the post-thaw phase, treatment proceeds as laid out in the Box.
Experimental approaches to the treatment of frostbite
Hyperbaric oxygen therapy
The literature on the treatment of frostbite contains no explicit recommendation of hyperbaric oxygen therapy. No superiority with regard to cell death could be demonstrated in controlled experimental animal studies. Individual case reports have described a favorable clinical outcome after hyperbaric oxygen therapy (23). There is insufficient evidence to justify a general treatment recommendation (24).
A controlled experimental animal study on rabbit ears showed that sympathectomy within 24 h of injury led to increased cell survival (25). A controlled prospective study in humans—without frostbite—revealed that a peripheral nerve blockade achieved significant increases in skin temperature and perfusion of the fingers. In a series of three cases of frostbite of the fingers, an increase of 0.8 to 1.3 °C in skin temperature was observed after selective sympathectomy (26). Sympathectomy within 24 h of injury thus appears to show promise for the treatment of frostbite. Performed later, however, sympathectomy exerts no positive influence on tissue survival (27). Sympathectomy can be achieved surgically or a catheter can be inserted for selective nerve blockade by means of drugs. In the acute treatment of frostbite injuries, local medicinal plexus blockade is the treatment of choice.
The administration of heparin in frostbite is indicated only when no risk factors for deep vein thrombosis are present (28).
A retrospective study showed that the use of tissue plasminogen activator within 24 h of injury was associated with a reduction in the rate of amputation of fingers or toes from 41% to 10% (29). Another retrospective study, in which 11 patients with scintigraphically confirmed perfusion disorders were treated with tissue plasminogen activator and heparin, reported amputation of 43 out of 73 underperfused fingers or toes threatened by amputation (30). The treatment selected was a bolus dose of 0.15 mg/kg tPA followed by 0.15 mg/kg/h tPA (maximum 100 mg) for 6 h (30, 31). Lysis is contraindicated by accompanying injuries such as fractures and craniocerebral trauma, thrombocytopenia, coagulation disorders, and pregnancy.
In animal experiments a significant reduction of the tissue damage in frostbite was achieved by combining slow warming with infusion of prostaglandin E1 (PGE1). In contrast, reserpine and the bolus administration of PGE1 showed no therapeutic benefit (32). In a clinical case series of five patients with second-degree and third-degree frostbite of the fingers or toes treated with iloprost (prostaglandin I2), amputation of the affected digits could be avoided. Perfusion was restored (33). In a comparative animal study, isosorbide dinitrate (ISDN) showed improvement in angiogenesis, an increase in vascular diameter, and reduction of edema formation (34).
Cold-induced injuries are often severe with far-reaching consequences, so the correct treatment needs to be given as soon as possible. If reperfusion is initially not achieved, treatment as described above should be supplemented by additional measures, depending on the patient's clinical situation; the indications must be carefully assessed. While the predominant symptoms in the posthyperemic phase of NFCI are chronic pain and paresthesia, the greatest dangers for patients who have suffered frostbite are loss of function and the possible necessity of amputation (Figure 4).
The initial classification of frostbite injuries according to the above-mentioned degrees of severity permits only limited conclusions with regard to the extent of tissue loss that has to be expected and the treatment that is then indicated (10). In the absence of signs of infection, wound healing or the appearance of clear demarcation in the affected area should be monitored over a period of weeks.
New treatment approaches have shown promise in experimental studies and case reports.
The treatment strategies for frostbite and NFCI presented here correspond to recommendation strength C. No recommendation grade can yet be assigned for the alternative treatment approaches, because there is no general consensus as to their value and they have not been sufficiently validated by studies. If warming does not result in reperfusion of the affected tissues, these procedures should be employed with regular monitoring of perfusion by Doppler sonography, angiography, or checking for a pulse. Nothing is yet known about combinations of the various procedures. More studies are needed before further treatment recommendations can be formulated. Basic recommendations are provided by the Wilderness Medical Society Practice Guidelines (20, 40).
Although some interesting and plausible options for the treatment of frostbite have been described, the level of evidence is very low. Lysis seems to be distinctly superior to the other approaches.
Apart from further investigation into various promising experimental approaches, such as the use of tissue plasminogen activator, prostaglandin E1 (PGE1), iloprost (prostaglandin I2), or isosorbide dinitrate (ISDN), prospective randomized clinical trials are required to develop guidelines and treatment standards.
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 5 August 2014, revised version accepted on
13 April 2015.
Translated from the original German by David Roseveare.
Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil
Universitätsklinikum der Ruhr-Universität Bochum
44789 Bochum, Germany
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