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Frostbite: experimental and clinical evaluations of treatment
Journal of Wilderness Medicine 1, 27-32 (1990)
Frostbite: experimental and clinical evaluations of treatment. J.P. HEGGERS*, L.G. PHILLIPS, R.L. McCAULEY and M.e. ROBSON. University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX, USA.
Based on experimental and clinical data, this review emphasizes the need for proper treatment of frostbite injuries. Experimentally employed anti-eicosanoid therapy in the modified Weatherly White model enhanced tissue survival, as each agent's inhibitory properties became more specific, when compared to controls. Topical methylprednisolone had a 17.5% tissue survival, while aspirin, Aloe vera cream and methimazole had 22.5%, 28.2% and 34.3% survival, respectively (p < 0.05). One hundred fifty-four (154) humans were evaluated as to therapeutic modalities; 56 were treated with topical Aloe vera cream and systemic ibuprofen, while 98 were treated with other modalities. Patient demographics were similar. However, hospital stay, tissue loss and morbidity were significantly (p < 0.001) reduced in the Aloe plus ibuprofen group when compared to the other therapeutic modalities, average 13 days v. 20 days, 79.9% healed v. 32.7% healed, and 7% morbidity v. 32.7% morbidity. Tissue loss from frostbite can be reduced if topical Aloe vera and systemic ibuprofen are employed as adjunctive therapies.
Key words: frostbite, anti-thromboxane, Aloe vera, cyclo-oxygenase inhibitors, eicosanoids, prostaglandins
Introduction
Progressive dermal necrosis is initiated by a traumatic insult to the integrity of the host's tissue, triggering a variety of mediators which are either beneficial or detrimental [1-5]. A thermal insult to the tissue can precipitate such a response. Thermal injuries encompass both ambient and tissue temperatures below 32°F and above llO°F. An important clinical and scientific question is whether the mechanism of tissue necrosis could be similar in both injuries. Our previous studies evaluating blister fluid from burns clearly showed the presence of the eicosanoids formerly termed prostaglandins or PGE z, PGFz and TxA z [5,6]. These earlier investigations evaluating burn blister fluid provided insight into the process of progressive dermal ischaemia [5,6]. However, analysis at that time could only provide a partial image of mediators responsible for progressive dermal necrosis, since the techniques were only capable of measuring the stable eicosanoids PGEz and PGFz· Consequently, it originally appeared that PGE z contributed to the necrosis seen in the thermal injury [7]. However, this subsequently did not appear to be the case. Our evaluation of burn blister fluid showed a low level of PGE z, with an elevated level of TxA z, the latter which could be the prime initiator of progressive ischaemia [5]. After *To whom correspondence should be addressed at: Shriners Burns Institute, 610 Texas Avenue, Galveston, Texas 77550, USA. 0953-9859/90 $03.00
+ .12 © 1990 Chapman and Hall Ltd.
28
Heggers et al.
pharmacological manipulation of the eicosanoid cascade, we confirmed that TxA z inhibition enhanced tissue survival in the burn wound [1,5]. Therefore, we wondered if the tissue necrosis seen in frostbite was mediated in the same fashion. We first examined fluid aspirated from frostbite blisters. Uniquely enough, the results were comparable to those measured from burn blister fluid, with PGE z and TxA z remarkably increased. Additionally, PGF za was elevated [8]. Our next experimental study was intended to examine our hypothesis by inhibiting thromboxane production. We proposed that progressive dermal ischaemia caused by TxA z release could be prevented in the frostbite injury as it could in burns [3,4,6,8]. In order to confirm our hypothesis regarding the reversal of progressive dermal ischaemia, we examined the influence of eicosanoid inhibitors in controlling tissue loss in an experimental frostbite model. Based on the experimental evidence and previous clinical trials, we re-evaluated our data. Methods
Experimental method A modified Weatherly-White frostbite model was created in 20 New Zealand white rabbits [9]. Rabbits were anaesthetized with I.M. fentanyl and droperidol. The hair of the ear was shaved off and a thermistor-probe was inserted subcutaneously, with the tip placed 2 cm from the distal end of the ear. The ear was then placed in the inner chamber of a double-chambered vessel containing 50% and 95% ethanol, respectively. Solid COz was added to the outer chamber when the ear was placed in the inner chamber. The freezing periods were about 20 min to ensure 100% tissue loss if the ear was left untreated. Treated groups were divided into the following therapeutic regimens:
Group Group Group Group Group
III III IV V-
Topical 1% methylprednisolone acetate ASA 50 mg kg-I, P.O. Topical Aloe vera cream (70% concentration) Methimazole, 1 mg kg-I, P.O. Non-treatment controls
These anti-eicosanoids were selected for their specificity of inhibition of the eicosanoid cascade. Methylprednisolone prevents phospolipid conversion to arachidonic acid by inhibiting the enzymatic action of phospholipase A. Aspirin prevents the conversion of arachidonic acid to PGHz by inhibiting cyclo-oxygenase. Both Aloe vera and methimazole prevent the conversion of PGHz to TxA z by inhibiting thromboxane synthetase. Treatment regimens were administered immediately after the ears were rewarmed in a 40°C water bath and continued every 8 h for a period of 96 h. Tissue survival was recorded by planimetry. The injured tissue was graphed as a schematic and the area was determined by a computerized digitizer pad. A non-treatment group served as a control. Clinical method Two distinct patient populations were treated from 1982 to 1985 at Detroit Receiving Hospital (ORH). Group 1 consisted of 56 patients admitted to the Burn Center at ORH from October 1983 to the winter of 1985, who were treated with our specific frostbite protocol. This therapeutic approach was based on our previous experimental and clinical data [10] (Table 1). Group 2 consisted of 98 patients who were admitted to other
Frostbite treatment
29
Table 1. DRH-UHCBC frostbite protocol.
(1) Patients with frostbite injuries are admitted to the DRH-UHCBC. (2) On admission, the affected area(s) will be rapidly rewarmed in circulating warm water (104108° F) for 15-30 min. Patients presenting 24 h after injury will not be rewarmed. (3) On completion of rewarming, the affected parts will be treated as follows:
(a) White or clear blisters will be debrided and topical treatment with Aloe vera (Dermaide AloeR ) every six hours will be instituted. Dermaide AloeR is a topical, cream-based, aqueous extract of Aloe vera at 70% concentration. Other aqueous extracts of Aloe vera at concentrations ~ 70% may be used provided they contain no other added substances which would counteract the properties of Aloe vera (i.e. alcohols, perfumes, salicylates, etc.) or prevent maximum penetration of the extract to the injured area. (b) Hemorrhagic blisters will be left intact and topical Aloe vera (Dermaide AloeR ) every six hours will be instituted. Hemorrhagic blister fluid is diagnostic of a full-thickness injury with extravasation from the subdermal plexus. If debrided, the subcutaneous fat and deep structures will be exposed, dessicate, and necrose. (c) Elevation of the affected part(s) with splinting as indicated. (d) Tetanus prophylaxis; immune globulin is required if the patient has never been immunized, or if the last booster was more than 10 years ago. (e) Analgesia (IV or 1M morphine or meperidine) as indicated. (f) Unless contraindicated by medical history, ibuprofen 12 mg kg- 1 PO per day; ketoprofen, a non-specific eicosanoid blocker, is less effective than the blocker of only deleterious compounds. (g) Penicillin: 500000 units every 6 h IV or 1M until oedema resolves. (h) Daily hydrotherapy.
services at DRH and treated with a wide variety of therapeutic modalities, which included either individually or in combination warm saline, hydrotherapy, silver sulfadiazine or mafenide acetate dressings, debridement of all frostbitten tissue and blisters, elevation of affected parts whenever possible, and narcotic agents for analgesia. Patient characteristics of both groups were similar at the time of admission (Table 2).
Results
Experimental study All control animals sloughed 100% of the frostbitten ear tissue. All treatment groups showed a statistically significant improvement when compared to the control group (p < 0.05). The results of therapy on tissue survival in descending order were as follows: methimazole 34.3%, Aloe vera 28.2%, aspirin 22.5% and methylprednisolone acetate 17.5%.
Clinical Study or Evaluations Of the 56 patients treated on the frostbite protocol, 32 were acute admissions, 24 were subacute ( > 24 h old) and five were chronic (one or more previous episodes) frostbite cases [10,11]. The average age for patients on the frostbite protocol was 43.5 years (range 17 to 82 years). Eighteen patients suffered 1st degree frostbite, 25 suffered 2nd
30
Heggers et al.
Table 2. Data for protocol-treated patients compared with data from non-protocol-treated
patients. Protocol Total patients Degree of injury 1st degree 2nd degree 3rd degree Average age (years) Range Sex Hospital stay (days) Acute admissions Subacute admissions Morbidity Healed without tissue loss Healed with tissue loss Amputation
56*
Non-protocol 98§
18 25 13 43.5 17-82 years 46 F, 21 M
51 36 48.5 18-82 years 91 F, 7M
8.5 (32) 14.9 (24)+
17.5 (56) 19.0 (42)
67.9%* 25.0% 7.0%
32.7% 34.6% 32.7%
11
*Patients admitted to the Burn Center at DRH. +(number of patients). *p < 0.001, includes all groups in the protocol treated patients. §Patients admitted to services other than the Burn Center at DRH.
degree frostbite, and 13 suffered 3rd degree injury (Table 1). The acute admissions accumulated a mean hospital stay of 8.5 days, subacute admissions required 14.9 days, and chronic frostbite cases required 18.5 days (Table 1). In this group of patients, 67.9% healed without tissue loss, 25.0% healed with some tissue loss, and only 7% required amputation (p < 0.001) (Table 2). Frostbitten portions of the body were equally distributed among the ears, feet, and hands [11]. The 98 patients treated by other services with different therapeutic modalities included 56 acute cases and 42 subacute cases, of which 14 patients presented with chronic frostbite. The average age for this group was 48.5 years (range, 18 to 82 years). Eleven patients suffered 1st degree frostbite, 51 suffered 2nd degree frostbite, and 36 suffered 3rd degree frostbite (Table 1). The acute admissions required a mean hospital stay of 17.5 days, the subacute required 19.0 days, and chronic frostbite cases required 22.6 days (Table 1). Of these 98 patients, 32.7% healed without tissue loss, 34.6% healed with some tissue loss, and 32.7% required amputation (Table 1). Those portions of the body frostbitten in this group had a similar body distribution to the protocol group [11]. Discussion Pathophysiology offrostbite Understanding the pathophysiology of frostbite allows one to comprehend the rationale for treatment and to realize why treatment regimens attempted in the past have had
Frostbite treatment
31
limited success. The pathophysiology can be divided into two specific phases: the immediate phase secondary to ice crystal formation in the tissue, and the delayed phase that results in progressive dermal ischaemia and tissue loss. When ice crystals form in tissue, water is drawn out of the cells into the extravascular spaces. As these crystals expand, they cause mechanical destruction of cells. The intracellular electrolyte concentration increases drastically, initiating cellular destruction. Endothelial cells are damaged, causing a loss of vascular integrity, leading to local oedema and loss of nutritive flow [6]. However, initial ice crystal formation in the tissue is not the most damaging. It is partial thawing and refreezing that causes the most severe injury. In addition, cold produces arteriolar vasoconstriction and tissue ischaemia. With thawing, arterioles reopen and blood flow is reestablished, with reactive hyperaemia. However, after more severe injury or after repeated thaw-freeze cycles, a progressive thrombotic phase occurs [10]. The progressive phase is due to progressive dermal ischaemia, very much like that following a thermal burn. Grossheim [12] showed changes in cold injury to be similar to those caused by inflammatory mediators responsible for progressive dermal ischaemia in burn wounds. He evaluated blister fluids from cases of hand frostbite and discovered levels of PgE 2, PgF2a , and TxA 2• The vasoconstricting, platelet-aggregating and leukocyte-adhesive prostanoids (PgF 2a and TxA 2) were markedly elevated. The investigators postulated that massive oedema following cold injury described by Merryman [13] was due either to leakage of proteins caused by release of these prostaglandins and thromboxanes, or secondarily due to white blood cells adhering in the capillaries, in some combined effect with subsequent increased hydrostatic pressure. Most frostbite patients experience pain due to direct cold injury to the nerves. Consequently, intra-arterial reserpine is of little value as an analgesic. Prostaglandins are essential in the normal maturation processes of the skin, particularly in the relationship of PGE 2 and cyclic AMP. Although PGE 2 is a vasodilator and PGF2a a vasoconstrictor, they maintain a steady state relationship through PGE 2 9-ketoreductase. When the host needs more PGE2 , PGF2a converts to PGE 2 through this enzyme and NADPH. Conversely, NADP+ and 9-keto-reductase produce PGF2a [7]. Low concentrations of the enzyme PGE 2 9-keto-reductase are present in normal skin. The presence of this enzyme complex indicates active biologic processes. Thus, our hypothesis of a steady-state or equilibrium relationship between PGE 2 and PGF2a to maintain normal cell function and cell integrity is substantiated. Consequently, any other inhibitors of the arachidonic cascade, such as ketoprofen, would be detrimental to this equilibrium. Attempts to reverse the injury with other modalities have not been successful. Attempts to re-establish or maintain circulation with anticoagulants, sympatholytics or sympathomimetics will not revive dead tissue. These agents cannot restore circulation once ice crystals have formed in the cells. In addition, these agents work on larger vessels. The tissue necrosis which occurs from derangement of the microcirculation is not alleviated by manipulation of the macrocirculation. Hyperbaric oxygen (HBO) therapy can increase tissue oxygenation, but will not reverse ice crystal formation within individual cells. It is our opinion that short-term HBO therapy cannot counteract the continuous bombardment by eicosanoids released as by-products of dying cell membranes. Therefore, based on this foundation of information, we designed a protocol aimed
32
Heggers et al.
specifically at inhibiting the local ischaemic effects caused by thromboxane and systemically controlling other prostanoids with ibuprofen [11]. The data clearly indicate that patients treated under this protocol had far less tissue loss (67.9% v. 32.7%), reduction in morbidity, (7.0% v. 32.7% amputation) (p < 0.001), and reduction in hospital stay (Table 1). Conclusions The therapeutic approach used to prevent progressive dermal necrosis due to the frostbite injury was designed to actively inhibit localized production of TxA 2 and to systemically control prostanoid production. This approach was based on experimental and clinical data supporting the hypothesis that TxA 2 is the major mediator of progressive dermal ischaemia. Ibuprofen was substituted for aspirin because aspirin irreversibly inhibits cyclooxygenase activity, which is necessary for PGE 2 and PGF 2a production. Our modified frostbite protocol reduced hospital stay and morbidity when compared to other therapeutic approaches. This protocol also reduces the incidence of frostbite arthritis, since it reduces pain and oedema and allows greater and earlier range of motion during rehabilitation, with less long term stiffness. References 1. 2.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Noble, G.H., Robson, M.e. and Krizek, TJ. Dermal ischemia in bum wound. J. Surg Res 1977; 23,117-25. Robson, M.e., DelBeccaro, E.J. and Heggers, J.P. The effect of prostaglandins on the dermal microcirculation after burning and the inhibition of the effect by specific pharmacologic agents. Piast ReconstrSurg 1979; 63, 781-87. DelBeccaro, E.J., Robson, M.e., Heggers, J.P., et ai. The use of specific thromboxane inhibitors to preserve the dermal microcirculation after burning. Surgery 1980; 87, 137-41. Robson, M.e., DelBeccaro, EJ., Heggers, J.P., et ai. Increasing dermal perfusion after burning by decreasing thromboxane production. J. Trauma 1980; 20, 722-25. Heggers, J.P., Ko, F., Robson, M.e., et ai. Evaluation of blister fluid. Piast Reconstr Surg 1980; 65, 798-804. Robson, M.C. and Heggers, J.P. Prostanoid derivatives in the thermal injury. In Boswick, J. ed. The Art and Science of Burn Care. Rockville, Maryland: Aspen Publishers, Inc., 1987: 275-84. Arturson, G. Prostaglandins in human bum wound secretion. Burns 1977; 3, 112-18. Robson, M.e. and Heggers, J.P. Evaluation of hand frostbite blister fluid as a clue to pathogenesis. J Hand Surg 1981; 6, 43-7. Raine, T.J., London, M.D., Goluch, L., et ai. Antiprostaglandins and antithromboxanes for treatment of frostbite. Surg Forum 1980; 31, 557-9. McCauley, R.L., Hing, D.N., Robson, M.e., et ai. Frostbite injuries: a rational approach based on the pathophysiology. J Trauma 1983; 23,143-7. Heggers, J.P., Robson, M.e., Manavalen, K., et ai. Experimental and Clinical Observations on Frostbite. Ann Emerg Med 1987; 16,1056-62. Grossheim, R.L. Hypothermia and frostbite treated with peritoneal dialysis. Aiaska Med 1973; 15,53-5. Merryman, H.T. Mechanisms of freezing in living cells and tissues. Science 1956; 124: 515.
Frostbite: experimental and clinical evaluations of treatment. J.P. HEGGERS*, L.G. PHILLIPS, R.L. McCAULEY and M.e. ROBSON. University of Texas Medical Branch and Shriners Burns Institute, Galveston, TX, USA.
Based on experimental and clinical data, this review emphasizes the need for proper treatment of frostbite injuries. Experimentally employed anti-eicosanoid therapy in the modified Weatherly White model enhanced tissue survival, as each agent's inhibitory properties became more specific, when compared to controls. Topical methylprednisolone had a 17.5% tissue survival, while aspirin, Aloe vera cream and methimazole had 22.5%, 28.2% and 34.3% survival, respectively (p < 0.05). One hundred fifty-four (154) humans were evaluated as to therapeutic modalities; 56 were treated with topical Aloe vera cream and systemic ibuprofen, while 98 were treated with other modalities. Patient demographics were similar. However, hospital stay, tissue loss and morbidity were significantly (p < 0.001) reduced in the Aloe plus ibuprofen group when compared to the other therapeutic modalities, average 13 days v. 20 days, 79.9% healed v. 32.7% healed, and 7% morbidity v. 32.7% morbidity. Tissue loss from frostbite can be reduced if topical Aloe vera and systemic ibuprofen are employed as adjunctive therapies.
Key words: frostbite, anti-thromboxane, Aloe vera, cyclo-oxygenase inhibitors, eicosanoids, prostaglandins
Introduction
Progressive dermal necrosis is initiated by a traumatic insult to the integrity of the host's tissue, triggering a variety of mediators which are either beneficial or detrimental [1-5]. A thermal insult to the tissue can precipitate such a response. Thermal injuries encompass both ambient and tissue temperatures below 32°F and above llO°F. An important clinical and scientific question is whether the mechanism of tissue necrosis could be similar in both injuries. Our previous studies evaluating blister fluid from burns clearly showed the presence of the eicosanoids formerly termed prostaglandins or PGE z, PGFz and TxA z [5,6]. These earlier investigations evaluating burn blister fluid provided insight into the process of progressive dermal ischaemia [5,6]. However, analysis at that time could only provide a partial image of mediators responsible for progressive dermal necrosis, since the techniques were only capable of measuring the stable eicosanoids PGEz and PGFz· Consequently, it originally appeared that PGE z contributed to the necrosis seen in the thermal injury [7]. However, this subsequently did not appear to be the case. Our evaluation of burn blister fluid showed a low level of PGE z, with an elevated level of TxA z, the latter which could be the prime initiator of progressive ischaemia [5]. After *To whom correspondence should be addressed at: Shriners Burns Institute, 610 Texas Avenue, Galveston, Texas 77550, USA. 0953-9859/90 $03.00
+ .12 © 1990 Chapman and Hall Ltd.
28
Heggers et al.
pharmacological manipulation of the eicosanoid cascade, we confirmed that TxA z inhibition enhanced tissue survival in the burn wound [1,5]. Therefore, we wondered if the tissue necrosis seen in frostbite was mediated in the same fashion. We first examined fluid aspirated from frostbite blisters. Uniquely enough, the results were comparable to those measured from burn blister fluid, with PGE z and TxA z remarkably increased. Additionally, PGF za was elevated [8]. Our next experimental study was intended to examine our hypothesis by inhibiting thromboxane production. We proposed that progressive dermal ischaemia caused by TxA z release could be prevented in the frostbite injury as it could in burns [3,4,6,8]. In order to confirm our hypothesis regarding the reversal of progressive dermal ischaemia, we examined the influence of eicosanoid inhibitors in controlling tissue loss in an experimental frostbite model. Based on the experimental evidence and previous clinical trials, we re-evaluated our data. Methods
Experimental method A modified Weatherly-White frostbite model was created in 20 New Zealand white rabbits [9]. Rabbits were anaesthetized with I.M. fentanyl and droperidol. The hair of the ear was shaved off and a thermistor-probe was inserted subcutaneously, with the tip placed 2 cm from the distal end of the ear. The ear was then placed in the inner chamber of a double-chambered vessel containing 50% and 95% ethanol, respectively. Solid COz was added to the outer chamber when the ear was placed in the inner chamber. The freezing periods were about 20 min to ensure 100% tissue loss if the ear was left untreated. Treated groups were divided into the following therapeutic regimens:
Group Group Group Group Group
III III IV V-
Topical 1% methylprednisolone acetate ASA 50 mg kg-I, P.O. Topical Aloe vera cream (70% concentration) Methimazole, 1 mg kg-I, P.O. Non-treatment controls
These anti-eicosanoids were selected for their specificity of inhibition of the eicosanoid cascade. Methylprednisolone prevents phospolipid conversion to arachidonic acid by inhibiting the enzymatic action of phospholipase A. Aspirin prevents the conversion of arachidonic acid to PGHz by inhibiting cyclo-oxygenase. Both Aloe vera and methimazole prevent the conversion of PGHz to TxA z by inhibiting thromboxane synthetase. Treatment regimens were administered immediately after the ears were rewarmed in a 40°C water bath and continued every 8 h for a period of 96 h. Tissue survival was recorded by planimetry. The injured tissue was graphed as a schematic and the area was determined by a computerized digitizer pad. A non-treatment group served as a control. Clinical method Two distinct patient populations were treated from 1982 to 1985 at Detroit Receiving Hospital (ORH). Group 1 consisted of 56 patients admitted to the Burn Center at ORH from October 1983 to the winter of 1985, who were treated with our specific frostbite protocol. This therapeutic approach was based on our previous experimental and clinical data [10] (Table 1). Group 2 consisted of 98 patients who were admitted to other
Frostbite treatment
29
Table 1. DRH-UHCBC frostbite protocol.
(1) Patients with frostbite injuries are admitted to the DRH-UHCBC. (2) On admission, the affected area(s) will be rapidly rewarmed in circulating warm water (104108° F) for 15-30 min. Patients presenting 24 h after injury will not be rewarmed. (3) On completion of rewarming, the affected parts will be treated as follows:
(a) White or clear blisters will be debrided and topical treatment with Aloe vera (Dermaide AloeR ) every six hours will be instituted. Dermaide AloeR is a topical, cream-based, aqueous extract of Aloe vera at 70% concentration. Other aqueous extracts of Aloe vera at concentrations ~ 70% may be used provided they contain no other added substances which would counteract the properties of Aloe vera (i.e. alcohols, perfumes, salicylates, etc.) or prevent maximum penetration of the extract to the injured area. (b) Hemorrhagic blisters will be left intact and topical Aloe vera (Dermaide AloeR ) every six hours will be instituted. Hemorrhagic blister fluid is diagnostic of a full-thickness injury with extravasation from the subdermal plexus. If debrided, the subcutaneous fat and deep structures will be exposed, dessicate, and necrose. (c) Elevation of the affected part(s) with splinting as indicated. (d) Tetanus prophylaxis; immune globulin is required if the patient has never been immunized, or if the last booster was more than 10 years ago. (e) Analgesia (IV or 1M morphine or meperidine) as indicated. (f) Unless contraindicated by medical history, ibuprofen 12 mg kg- 1 PO per day; ketoprofen, a non-specific eicosanoid blocker, is less effective than the blocker of only deleterious compounds. (g) Penicillin: 500000 units every 6 h IV or 1M until oedema resolves. (h) Daily hydrotherapy.
services at DRH and treated with a wide variety of therapeutic modalities, which included either individually or in combination warm saline, hydrotherapy, silver sulfadiazine or mafenide acetate dressings, debridement of all frostbitten tissue and blisters, elevation of affected parts whenever possible, and narcotic agents for analgesia. Patient characteristics of both groups were similar at the time of admission (Table 2).
Results
Experimental study All control animals sloughed 100% of the frostbitten ear tissue. All treatment groups showed a statistically significant improvement when compared to the control group (p < 0.05). The results of therapy on tissue survival in descending order were as follows: methimazole 34.3%, Aloe vera 28.2%, aspirin 22.5% and methylprednisolone acetate 17.5%.
Clinical Study or Evaluations Of the 56 patients treated on the frostbite protocol, 32 were acute admissions, 24 were subacute ( > 24 h old) and five were chronic (one or more previous episodes) frostbite cases [10,11]. The average age for patients on the frostbite protocol was 43.5 years (range 17 to 82 years). Eighteen patients suffered 1st degree frostbite, 25 suffered 2nd
30
Heggers et al.
Table 2. Data for protocol-treated patients compared with data from non-protocol-treated
patients. Protocol Total patients Degree of injury 1st degree 2nd degree 3rd degree Average age (years) Range Sex Hospital stay (days) Acute admissions Subacute admissions Morbidity Healed without tissue loss Healed with tissue loss Amputation
56*
Non-protocol 98§
18 25 13 43.5 17-82 years 46 F, 21 M
51 36 48.5 18-82 years 91 F, 7M
8.5 (32) 14.9 (24)+
17.5 (56) 19.0 (42)
67.9%* 25.0% 7.0%
32.7% 34.6% 32.7%
11
*Patients admitted to the Burn Center at DRH. +(number of patients). *p < 0.001, includes all groups in the protocol treated patients. §Patients admitted to services other than the Burn Center at DRH.
degree frostbite, and 13 suffered 3rd degree injury (Table 1). The acute admissions accumulated a mean hospital stay of 8.5 days, subacute admissions required 14.9 days, and chronic frostbite cases required 18.5 days (Table 1). In this group of patients, 67.9% healed without tissue loss, 25.0% healed with some tissue loss, and only 7% required amputation (p < 0.001) (Table 2). Frostbitten portions of the body were equally distributed among the ears, feet, and hands [11]. The 98 patients treated by other services with different therapeutic modalities included 56 acute cases and 42 subacute cases, of which 14 patients presented with chronic frostbite. The average age for this group was 48.5 years (range, 18 to 82 years). Eleven patients suffered 1st degree frostbite, 51 suffered 2nd degree frostbite, and 36 suffered 3rd degree frostbite (Table 1). The acute admissions required a mean hospital stay of 17.5 days, the subacute required 19.0 days, and chronic frostbite cases required 22.6 days (Table 1). Of these 98 patients, 32.7% healed without tissue loss, 34.6% healed with some tissue loss, and 32.7% required amputation (Table 1). Those portions of the body frostbitten in this group had a similar body distribution to the protocol group [11]. Discussion Pathophysiology offrostbite Understanding the pathophysiology of frostbite allows one to comprehend the rationale for treatment and to realize why treatment regimens attempted in the past have had
Frostbite treatment
31
limited success. The pathophysiology can be divided into two specific phases: the immediate phase secondary to ice crystal formation in the tissue, and the delayed phase that results in progressive dermal ischaemia and tissue loss. When ice crystals form in tissue, water is drawn out of the cells into the extravascular spaces. As these crystals expand, they cause mechanical destruction of cells. The intracellular electrolyte concentration increases drastically, initiating cellular destruction. Endothelial cells are damaged, causing a loss of vascular integrity, leading to local oedema and loss of nutritive flow [6]. However, initial ice crystal formation in the tissue is not the most damaging. It is partial thawing and refreezing that causes the most severe injury. In addition, cold produces arteriolar vasoconstriction and tissue ischaemia. With thawing, arterioles reopen and blood flow is reestablished, with reactive hyperaemia. However, after more severe injury or after repeated thaw-freeze cycles, a progressive thrombotic phase occurs [10]. The progressive phase is due to progressive dermal ischaemia, very much like that following a thermal burn. Grossheim [12] showed changes in cold injury to be similar to those caused by inflammatory mediators responsible for progressive dermal ischaemia in burn wounds. He evaluated blister fluids from cases of hand frostbite and discovered levels of PgE 2, PgF2a , and TxA 2• The vasoconstricting, platelet-aggregating and leukocyte-adhesive prostanoids (PgF 2a and TxA 2) were markedly elevated. The investigators postulated that massive oedema following cold injury described by Merryman [13] was due either to leakage of proteins caused by release of these prostaglandins and thromboxanes, or secondarily due to white blood cells adhering in the capillaries, in some combined effect with subsequent increased hydrostatic pressure. Most frostbite patients experience pain due to direct cold injury to the nerves. Consequently, intra-arterial reserpine is of little value as an analgesic. Prostaglandins are essential in the normal maturation processes of the skin, particularly in the relationship of PGE 2 and cyclic AMP. Although PGE 2 is a vasodilator and PGF2a a vasoconstrictor, they maintain a steady state relationship through PGE 2 9-ketoreductase. When the host needs more PGE2 , PGF2a converts to PGE 2 through this enzyme and NADPH. Conversely, NADP+ and 9-keto-reductase produce PGF2a [7]. Low concentrations of the enzyme PGE 2 9-keto-reductase are present in normal skin. The presence of this enzyme complex indicates active biologic processes. Thus, our hypothesis of a steady-state or equilibrium relationship between PGE 2 and PGF2a to maintain normal cell function and cell integrity is substantiated. Consequently, any other inhibitors of the arachidonic cascade, such as ketoprofen, would be detrimental to this equilibrium. Attempts to reverse the injury with other modalities have not been successful. Attempts to re-establish or maintain circulation with anticoagulants, sympatholytics or sympathomimetics will not revive dead tissue. These agents cannot restore circulation once ice crystals have formed in the cells. In addition, these agents work on larger vessels. The tissue necrosis which occurs from derangement of the microcirculation is not alleviated by manipulation of the macrocirculation. Hyperbaric oxygen (HBO) therapy can increase tissue oxygenation, but will not reverse ice crystal formation within individual cells. It is our opinion that short-term HBO therapy cannot counteract the continuous bombardment by eicosanoids released as by-products of dying cell membranes. Therefore, based on this foundation of information, we designed a protocol aimed
32
Heggers et al.
specifically at inhibiting the local ischaemic effects caused by thromboxane and systemically controlling other prostanoids with ibuprofen [11]. The data clearly indicate that patients treated under this protocol had far less tissue loss (67.9% v. 32.7%), reduction in morbidity, (7.0% v. 32.7% amputation) (p < 0.001), and reduction in hospital stay (Table 1). Conclusions The therapeutic approach used to prevent progressive dermal necrosis due to the frostbite injury was designed to actively inhibit localized production of TxA 2 and to systemically control prostanoid production. This approach was based on experimental and clinical data supporting the hypothesis that TxA 2 is the major mediator of progressive dermal ischaemia. Ibuprofen was substituted for aspirin because aspirin irreversibly inhibits cyclooxygenase activity, which is necessary for PGE 2 and PGF 2a production. Our modified frostbite protocol reduced hospital stay and morbidity when compared to other therapeutic approaches. This protocol also reduces the incidence of frostbite arthritis, since it reduces pain and oedema and allows greater and earlier range of motion during rehabilitation, with less long term stiffness. References 1. 2.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
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