Frostbite of both first digits of the foot treated with

UHM 2014, Vol. 41, No. 1 – hBO2 for the tReaTmEnt of FROSTBITE

Frostbite of both first digits of the foot treated with delayed hyperbaric oxygen: A case report and review of literature Tom C.P.M. Kemper M.Sc. 1, Vincent M. de Jong M.D. 2, Helen A. Anema Ph.D. 3, Albert van den Brink M.D. 1, Robert A. van Hulst M.D. Ph.D. 1,4 1 Department

of Hyperbaric Medicine and Laboratory Experimental Intensive Care Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands 2 Department of Trauma Surgery, Academic Medical Center, Amsterdam, The Netherlands 3 Department of Public Health, Academic Medical Center, Amsterdam, The Netherlands 4 Diving Medical Center, Royal Netherlands Navy, Den Helder, The Netherlands CORRESPONDING AUTHOR: Tom C.P.M. Kemper – [email protected] ______________________________________________________________________________________________ ABSTRACT

Case report and review of literature: We present a Background: Frostbite is an uncommon event that case report of a woman with deep frostbite of the toes can occur from exposure to temperatures below treated with hyperbaric oxygen therapy, after a delay -4°C and can lead to potential serious tissue damage of 21 days, with good results. No surgical intervention and necrosis. This in turn can result in debilitating was needed. A literature search revealed 17 human amputations in otherwise healthy people. The pathocase reports on frostbite and four animal studies in physiological mechanisms of frostbite have marked which hyperbaric oxygen was applied. All case similarities to those seen in thermal burns, ischemia/ reports showed positive effects, and in none of reperfusion injuries and crush injuries — i.e., nonthe cases was amputation necessary. In the animal healing wounds and inflammatory processes. These studies, two showed significant positive results injuries are commonly treated with hyperbaric oxygen regarding tissue loss and reduction of inflammatory therapy. markers, whereas two did not. Objectives: Evidence for treating frostbite with hyperConclusions: Based on our case report as well as baric oxygen (HBO2) is scarce, and to date HBO2 the literature and the mechanisms of hyperbaric is not a standard addition in the multidisciplinary oxygen, we make the recommendation that this care of freezing injuries. We aim to contribute to the therapy be considered as an addition to the multiavailable evidence with a case report and review the disciplinary treatment of frostbite, even after signiliterature to reassess the multidisciplinary treatment ficant delay of treatment. of frostbite injuries. _____________________________________________________________________________________________

INTRODUCTION Frostbite is an uncommon but potentially serious event that can occur from exposure to temperatures below -4°C and can lead to extensive tissue damage in otherwise healthy people who are (most likely) part of the working and sporting population [1]. Despite the increase in persons at risk (due, for example, to outdoor activities [2], homelessness [3]), data on the incidence and morbidity are scarce, large randomized clinical trials are not yet feasible and standard treatment guidelines based on a high level of evidence are lacking. A recent treatment guideline from the Wilderness Medical Society was based on a (systematic) literature-

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guided consensus process, encompassing a large number of international frostbite experts [4]. With respect to hyperbaric oxygen (HBO2) therapy it was concluded that, despite anecdotal evidence of positive effects in a few case reports [1,5,6], due to the absence of controlled trials the data are insufficient to recommend HBO2 therapy for frostbite. To contribute to the knowledge on treatment of this type of injury, we present a report of frostbite injury treated with HBO2 after a relatively long delay of 21 days. Also provided is an overview of the literature on the effectiveness of hyperbaric oxygen therapy in humans and in animal studies.

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UHM 2014, Vol. 41, No. 1 – hBO2 for the tReaTmEnt of FROSTBITE ________________________________________________________________________________________________________

FIGURE 1

CASE REPORT A 32-year-old female mountain climber was seen at the traumatology department with frostbitten toes after a 28-day climb in Nepal. On Day 21 of the climb, after a reasonably good night’s sleep, the group started the ascent to the summit, at a temperature of around -15°C. After reaching the summit, the party started the descent to high camp. During the descent the temperature rose, causing a throbbing pain in the toes of our patient. Back at high camp, both first digits of her feet had a white, cold, waxy appearance and she noticed a blister on her right big toe. After a short discussion with a fellow climber (a certified nurse) she decided to puncture the blister, which they thought was caused by friction. In Kathmandu, seven days after suffering frostbite, she was seen by two general practitioners (GPs) in the hotel, who diagnosed it as infected frostbite and prescribed 3000 mg co-fluampicil. Twelve days after onset she was seen at our department of traumatology, where we diagnosed deep frostbite with wet necrosis of the distal phalanx of both first digits of the foot. It was decided to start HBO2 as adjunct treatment, mainly because there is some (anecdotal) evidence that HBO2 therapy may be effective after delayed treatment.

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On Day 21 after the initial frostbite, the first session of HBO2 was begun. Treatments were for 90 minutes, 3 x 20 minutes at 100% O2 alternated with normal air, under 2.5 bar [7]. During initial sessions the patient experienced a tingling sensation in the affected area. After seven sessions the situation was reviewed and considerable improvement was observed. The wet necrosis dried, and the infection seemed to have subsided. Moreover, the demarcation line between viable and non-viable tissue progressed peripherally. Therefore, it was decided to resume HBO2 therapy for a total of 19 sessions. During treatment both nails were removed and a superficial debridement of necrotic tissue was performed. Eventually, the patient’s toes recovered almost completely, with a small cosmetic defect at the tips of both toes and nails, some impairment in flexion of the right first digit, and minor difficulty in maintaining balance while standing on one leg. In addition, our patient sometimes experiences pain in the skin and nails of both toes after long walks or climbing trips, or when exposed to cold. Figure 1 shows the patient’s toes at the first time she noticed the blister (Day 0), during HBO2 treatment and the final result.

T.C.P.M. Kemper, V.M. de Jong, H.A. Anema, A. van den Brink, R.A. van Hulst

UHM 2014, Vol. 41, No. 1 – hBO2 for the tReaTmEnt of FROSTBITE _______________________________________________________________________________________________________________________

Table 1. Data on 10 published case reports including 17 patients Reference Patient Age/ Classifi- Injury Delay Depth Co- Outcome years cation location & time treatment _______________________________________________________________________________________________________________________ Ledingham 15 2 patients* n.a n.a Fore part of n.a 27 hours n.a No loss of tissue 1 female both feet *other patient not documented _______________________________________________________________________________________________________________________ Smith 16 1 female 44 Deep Both feet n.a 2b/n.a/5d n.a All tissues were preserved, apart from a small defect 2x3 cm _______________________________________________________________________________________________________________________ Perrins 17 1 male 39 Deep Both legs to knee 12 4b/2x45m Low-mol. No amputations needed level and all hours /5d wt. dextran only superficial skin fingertips separation, cold sensitivity _______________________________________________________________________________________________________________________ Trippel 18 2 males 12,13 Deep Toes and distal n.a n.a n.a No tissue loss part of the foot _______________________________________________________________________________________________________________________ Ward 19 4 males 24-32 Deep n.a 5-10 2b/120m/19d Antibiotics n.a. days 1 patient rec’d nicotinyl alcohol _______________________________________________________________________________________________________________________ Cooke 20 3 patients n.a n.a n.a n.a n.a n.a n.a _______________________________________________________________________________________________________________________ 6 von Heimburg 1 male 11 Deep 6 fingers 7 2.4b/90m/14d Blister Complete healing days debridement, vaseline gauze, tetanus prophylaxis _______________________________________________________________________________________________________________________ Finderle 5 1 male 28 Deep Multiple toes 4 2.5b/90m/28d Antibiotics No amputations needed, days surgical shortening of distal phalanx of one toe _______________________________________________________________________________________________________________________ Folio 1 1 female 28 Deep All fingers of 14 n.a. Aloe vera gel No amputations, one both hands days slightly misshapen finger _______________________________________________________________________________________________________________________ Sever 21 1 male 37 Superficial Right hand None 2.4b/90m/14d Heparin, No amputations needed, and deep high-mol. hand healed with good wt. dextran, range of movement antibiotics _______________________________________________________________________________________________________________________

DISCUSSION Studies on the pathophysiology of frostbite have shown marked similarities in non-healing wounds and in inflammatory processes to those seen in thermal burns and crush injuries [2,8]. In our patient there was a delay of 21 days before treatment with HBO2. Together with the acquired infection and the fact that the frostbite involved the lower extremities, there was increased risk that surgical treatment would be necessary [2,9]. However, in our patient surgical intervention was prevented. Although positive outcomes after HBO2 therapy with a long delay of treatment have been reported, they are only narrative case studies (Table 1). The pathophysiological changes that arise during frostbite injuries occur in four phases: changes that develop during cooling, freeze-thaw, vascular stasis and the late ischemic phase [4]. Upon exposure to cold, tissues will respond by initiating vasoconstriction in order to

preserve the body’s core temperature; prolonged exposure will result in tissue ischemia [10]. The vasoconstriction is followed by vasodilatation, also known as the Hunting response [11]. This is an attempt by the body to protect the tissues from freezing, but has no effect when exposed to intense cooling [4]. During the freeze-thaw phase intracellular ice crystals are formed as a result of rapid freezing, or extracellular ice crystals can form during a slower freeze [4]. Intracellular ice crystal formation results in cell rupture and death [12], whereas extracellular ice crystal formation increases the oncotic pressure in the extracellular space, which leads to dehydration of cells [12].Upon prolonged freezing, cellular electrolyte shifts are observed, together with protein denaturation, intra- and extracellular pH changes and destruction of essential enzymes [10]. Prolonged cooling of the vascular content also encourages the formation of micro-

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UHM 2014, Vol. 41, No. 1 – hBO2 for the tReaTmEnt of FROSTBITE thrombi which lead to occlusion of the capillaries and ischemia due to an increase in viscosity [13] and severe structural damage in the endothelial lining. As a consequence, this results in an increased permeability of the vascular wall, with the formation of extravascular edema. During reperfusion, an increased formation of oxygen radicals is observed, as well as neutrophil activation and other inflammatory events [10]. An early response to thawing is activation of the arachidonic acid cascade, which leads to formation of prostaglandins and thromboxane. This is turn stimulates clotting and sludging in the microcirculation [12]. The late ischemic phase is a result of prolonged tissue ischemia and the inflammatory response, and is characterized by collapsing of the peripheral vascular system followed by microvascular and macrovascular thrombosis [10]. The beneficial effect of HBO2 in treating frostbite lies in alleviating adverse effect of cold-induced vascular changes [12]. HBO2 is expected to oxygenate the ischemic tissues by hyperoxygenating the plasma, which has the ability to diffuse through the sludged areas where red blood cells and white blood cells are not moving. The use of hyperbaric oxygen can result in arterial oxygen tensions of ≥ 2000 mmHg and oxygen tissue levels ≥ 400 mmHg [14]. Because local hypoxia leads to poor wound healing, adequate oxygen tension is a prerequisite for the collagen matrix and angiogenesis [15]. Hypoxia also predisposes wounds to infection, because the neutrophil-mediated killing of bacteria by free radicals is decreased. In reperfusion injury, neutrophils adhering to the wall of ischemic vessels release proteases and produce free radicals, leading to pathological vasoconstriction and tissue destruction. HBO2 inhibits neutrophil adherence and post-ischemic vasoconstriction in ischemic rat tissue [16]. The other most common complications of frostbite are chronic pain, dysesthesias and hypersensitivity to cold [13], which are probably due to damage to vascularity and peripheral nerves [13]. Whether HBO2 therapy might be beneficial in preventing these complications is not yet clear. Additional retrospective studies comparing late neuropathies in patients who received HBO2 therapy and those who did not could provide additional information. Frostbite should be classified using the simplified two-tier system in preference to the traditionally used four-degree classification scheme derived from thermal burn injury, as these categories are difficult to assess in the acute phase [11]. The simplified two-tier system consists of superficial frostbite without tissue loss, and

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deep frostbite in which tissue loss is expected [11]. HBO2 seems effective in the delayed treatment of frostbite, as described in several case reports with impressive results, even after a significant delay between onset of frostbite and treatment. The period 1963-2011 produced reports on 17 patients with frostbite injuries treated with hyperbaric oxygen; their clinical characteristics are summarized in Table 1 [1,5,6,15-21]. Most of these studies describe positive effects, and in none of the cases was an amputation required. Table 1 also shows the range of injuries, the large range in delay before HBO2 therapy and the use of several treatment tables for HBO2. Experimental studies have produced contradictory results. Of the four animal studies in which animals were severely injured but with different endpoints (tissue loss, inflammatory response) and all treated in the acute phase of the freezing injury, two studies showed a positive and significant effect of HBO2 therapy [22,25] whereas two did not [23,24]. The study of Okuboyu et al. [22] used rabbits. Animals’ paws were immersed in water at -20°C for 20 minutes and rapidly rewarmed in water of 42°C. The paws were dried, bandaged and the animals received prophylactic antibiotics. It was concluded that treatment immediately after thawing – for five days at two hours/day – gives significantly better results of tissue loss compared with one hour of HBO2 on a daily basis, or later than 24 hours after thawing [22]. Gage et al. [23] also conducted experiments on rabbits with frozen paws, where the temperatures ranged from -5°C to -40°C, and found no significant differences in tissue loss; the treatment protocol was twice a day at 2.5 bar with 100% oxygen for seven days. Hardenberg et al. [24] performed experiments with mice and frozen paws, frozen in -30°C for one or three minutes. They divided the mice into four groups, with slow and fast rewarming, and with and without HBO2 treatment. Tissue loss was determined on a scale from 0-5, where 0 signified no tissue loss and 5 full tissue loss. It was concluded that HBO2 had no significant positive effect on decreasing tissue damage in freezing injuries [24]. Finally, Uygur et al. [25] conducted experiments in rabbits where they froze the ears for three minutes in -25°C. Beginning one hour after injury, the animals were treated twice a day at 2.5 bar for 90 minutes over 14 days. The authors found a significant decrease in tissue loss (39%) as well as a positive effect of

T.C.P.M. Kemper, V.M. de Jong, H.A. Anema, A. van den Brink, R.A. van Hulst

UHM 2014, Vol. 41, No. 1 – hBO2 for the tReaTmEnt of FROSTBITE HBO2 on the inflammatory process as measured by a decrease in mast cells and neutrophils, and an increased level of prostaglandin I2 [25]. We postulate that, based on the mechanisms of hyperbaric oxygen, it would be worthwhile to consider adding HBO2 therapy to the multidisciplinary treatment of frostbite in the acute phase as well after a relatively longer delay (≥ one week). In the acute phase HBO2 has great potential benefit, with improved red blood cell rheological features, decreased edema, improved oxygenation, interrupted leukocyte adhesion and diminished lipid peroxidation. The delayed use of HBO2 therapy for frostbite is to prevent complications of non-healing wounds, aid in demarcation (not an approved HBO2 indication) and to help preserve threatened flaps and grafts after surgical interventions. A recent review by McIntosh et al. [4] presents a summary of field treatment and secondary hospital treatment, which includes systemic antibiotics, tetanus prophylaxis, analgetics and thrombolytic therapy. At this moment they consider that there is insufficient data to recommend HBO2 therapy for frostbite. Other promising treatment modalities for frostbite injuries are thrombolytic therapy [26,27,28,29,30,31] and prostacyclin therapy [28]. Gross et al. [26] concluded that patients with less than 24 hours of cold exposure, no evidence of multiple freeze/thaw cycles, no improvement with rapid rewarming, absent Doppler pulses in limbs and/or digits and absence of perfusion on angiography or technetium-99m triple-phase bone scanning, and without contraindications for tissue plasminogen activator (tPa) treatment should be con-

sidered for IV tPA. Moreover, a study by Cauchy et al. [28] found prostacyclin to be superior to prostacyclin plus tPA in frostbite, recommending the use of aspirin and prostacyclin after rapid rewarming over the use of tPA. However, tPA should still be considered depending on the individual case [28]. We believe HBO2 had a positive effect in our patient, as we believe it played a role in suppressing the infection and revitalizing the damaged tissues. It had an additional positive contribution in wound healing. Previous case reports are promising but anecdotal, and we realize that positive published results may be at risk of publication bias. Furthermore, animal studies show conflicting results; the freezing injuries inflicted in animals are more acute and intense compared with injuries found in the human population, where the frostbite usually develops more gradually. We believe the cold injury inflicted in the study animals resulted in irreversible damage due to the intensity of the freezing. Overall, the current evidence in the literature is scarce at best. Therefore, a systematic research program using animal models (with less severe injuries, more comparable to those found in the human population, extended with longer delays between injury and treatment) and human case reports is needed before HBO2 therapy can be considered to be the standard of care. Acknowledgment Special thanks to Johan de Wit for graphic design of Figure 1. The authors have declared that no conflict of interest exists submission. n

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