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The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study
Injury, Int. J. Care Injured (2006) 37, 638—641
www.elsevier.com/locate/injury
The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study Volkan Oztuna a,*, Metin M. Eskandari a, Sakir Unal b, Mehmet Colak a, Tuba Karabacak c a
Department of Orthopaedics, Mersin University School of Medicine, Ihsaniye Mah, 4935 Sokak No. 3, 33079 Mersin, Turkey b Department of Plastic and Reconstructive Surgery, Mersin University School of Medicine, Turkey c Department of Pathology, Mersin University School of Medicine, Turkey Accepted 20 February 2006
KEYWORDS Pentoxifylline; Skin; Degloving injury
Summary Background: Management of skin degloving injuries is still a problematic issue and the avulsed part of the skin may become necrotic. In this pilot study, we attempted to develop an experimental model for degloving injuries and investigated the efficacy of pentoxifylline, a well-known potent agent in enhancement of erythrocyte flexibility and tissue vascularization, in treatment of this injury model. Methods: Degloving injuries were created in 15 rats’ tails by circular puncturing of the skin at the middle of the tail and then applying moderate force to avulse the skin from the underlying tissue. Then, the skin was repaired back to its original position. No treatment was given in the first group (n = 6). In the second group (n = 3), 0.4 cm3 physiological serum was administered intraperitoneally for 10 days. In the third group (n = 6), intraperitoneal 25 mg/kg pentoxifylline was administered for 10 days. Tails were observed daily for 21 days and then examined histopathologically. Results: At the end of the study, the avulsed segment of the skin became cyanotic and ulcerated in the first and the second group, and in the third group, the skin was intact. In histopathological examination, loss of superficial ephitelium and dense infiltration of inflammatory cells were seen in groups 1 and 2, and the skin layers were normal in the group 3. Conclusion: Pentoxifylline improved tissue preservation and was proved to be highly beneficial in treatment of skin degloving injuries. # 2006 Elsevier Ltd. All rights reserved.
* Corresponding author at: Viransehir Mah. Moda Plaza, C blok, D: 10, Mersin 33190, Turkey. Tel.: +90 324 3374300x1161; fax: +90 324 3374305. E-mail address: [email protected] (V. Oztuna). 0020–1383/$ — see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2006.02.025
The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study
639
Introduction In skin avulsion injuries, as the subcutaneous vascular plexus is severed, the blood supply of the avulsed segment of the skin can be damaged. Attempts at suturing the skin back to its original position may lead to necrosis.5 Avulsed skin, in fact, constitutes a composite graft which includes the skin and the subcutaneous tissue. It is believed that survival of the graft depends on early establishment of circulation by direct vessel-to-vessel anastomosis between the graft and the recipient bed.6 In this condition, a pharmacological agent having the capability to improve the vascularisation is necessary. Pentoxifylline is a well-known potent agent in enhancement of tissue vascularisation due to its ability to increase red blood cell flexibility and improves the flow properties of blood by decreasing its viscosity.1,4 In this pilot study, we designed an experimental model for skin degloving injury and examine the efficacy of pentoxifylline in treatment of this injury model.
Materials and methods We used 15 male Spraque—Dawley male rats with a body-weight of between 230 and 300 g. The study began after permission was obtained from the Institutional Animal Research Council. The subjects were anaesthetised by an intramuscular injection of 50 mg/kg ketamine hydrochloride (Ketalar1; EWL Eczacıbas¸ı Warner Lambert Istanbul, Turkey). The injury was created by circular puncturing of the skin in the middle of the tail with an scalpel No. 11 and then applying moderate force distally to avulse the skin and subcutaneous tissue from the underlying tendinous and vascular tissue. The skin was separated in approximately 3 cm length but still attached to the distal tail (Fig. 1). Fifteen minutes after the injury, the skin was repaired with 4/0 vicryl. The first group (n = 6) was taken as the control group. In the second group (n = 3), 0.4 cm3 physiological serum (the same volume of liquid used in the third group) was administered intraperitoneally for 10 days to examine the possible therapeutic effect of fluid injection in terms of volumetric replacement. In the third group, 25 mg/kg (0.4 cm3) pentoxifylline (Trental, Aventis, USA), was administered intraperitoneally after repair, and then 25 mg/kg/day for 10 days. The colour of the skin and the status of the wound were observed daily for 21 days. At the end of the third week, tails were examined histopathologically.
Figure 1
Injury model: avulsion of the skin in rat’s tail.
Results In the first 2 days, all the tails were swollen and the avulsed segments of the skin were cyanotic and oedematous. After the third day, progressive deterioration in the colour of the avulsed segment of the skin was observed in the groups 1 and 2. On the 21st day, the boundary of the necrosis in groups 1 and 2 was approximately 3 cm in length in the avulsed segment of the skin. The distal part of the tail was still edematous (Fig. 2). In group 3, cyanosis and oedema disappeared after the third day and there was no necrotic area in the tails at the end of the study (Fig. 3). No wound infection occurred in the tails. In histopathological examination, the specimens were fixed in 10% formalin for 24 h and standard dehydration and parafin wax embedding procedures were used. Haematoxylin and eosin-stained slides were prepared by using standard methods. Skin lesions were classified by using the National Pressure Ulcer Advisory Panel (NPUAP)7 and staged from 0 to 4 according to following criteria–—Stage 0: normal skin; Stage I: non-blanchable erythema (inflammation) of intact skin the heralding lesion of skin ulceration; Stage 2: partial thickness skin lost involving epidermis, dermis, or both; Stage 3: full
640
V. Oztuna et al.
Figure 2 Necrotic segment of the skin of the tail in the groups 1 and 2.
Figure 5
Intact epidermis in the group 3 (H + E, 100).
thickness skin lost involving necrosis of subcutaneous tissue that may extend down to, but not through underlying fascia; Stage 4: full thickness skin lost with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures (e.g., tendon, joint capsule). Microscopically, in the groups 1 and 2 ulceration, loss of epidermis and superficial dermis and capillary proliferation was observed (Stage 2) (Fig. 4). The epidermis recovered its normal thickness and had no inflammation in the group 3 (stage 0) (Fig. 5).
Discussion Figure 3 group 3.
The skin was intact at the end of the study in
Figure 4 Ulceration and neutrophil accumulation in the groups 1 and 2 (H + E, 100).
In this pilot study, we created a skin degloving injury model, and then investigated the efficacy of pentoxifylline in this injury model and approved its positive effect on tissue viability by clinical and histopathological assessment. In trauma centres, clinicians encounter skin degloving injuries such as ring injuries and closed skin degloving injury of the extremities resulting from high-energy trauma with or without bony injury. Especially, in case of AO-IC 3 and AO-IC 4 closed fractures (circumscribed closed degloving injury of the skin),8 failure to care the soft tissue injuries can result in serious complications ranging from delayed wound healing to massive infection. To the best of our knowledge, there is no experimental skin degloving injury model described in the literature. We created a skin avulsion injury model in rat tails of which its shape allowed us to perform a circumferential avulsion of the skin. This model resembled a type I ring injury10 and it can be used as a standard model. In types II and III ring injuries, a perfect microsurgical treatment is needed for good results. However, in type I injuries, there is no
The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study specific management to protect the viability of the avulsed skin. We think that pentoxifylline can be used for this clinical scenario as it showed a protective effect on viability of the avulsed part of the skin. It may be also a potential agent for the treatment of closed skin degloving injuries of the extremities. It is believed that skin grafts can survive via formation of direct vascular anastomoses between the recipient and donor area. This process takes place before actual capillary invasion which usually takes 72 h.3 Herein, a pharmacological agent having capacity to improve the vascularisation is necessary in this critical period. As has been explained in several studies previously, pentoxifylline has multiple actions that enhance tissue survival. Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity and enhancing tissue oxygenation. The most well-known action of pentoxifylline is its ability to increase erythrocyte flexibility, allowing easier vascularisation.1,4,11 The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement are still to be defined. It has been proved that pentoxifylline enhances the blood flow in a testicular torsion model.9 It prevents the formation of skin necrosis resulting from infiltration of antitumor agents into subcutaneous tissues2 and enhances the flap survival in humans.1,11 In our study, pentoxifylline showed a protective effect on viability of the avulsed part of the skin. We think that in the first 72 h after injury, pentoxifylline improved erythrocyte flexibility and eased the formation of direct vascular anastomoses between the recipient and the donor area. It is evident from this study that pentoxifylline therapy resulted in significant improvement in
641
the degree of tissue preservation and proved to be highly beneficial in treatment of skin degloving injury model in rats. This experimental model may serve a standard technique that can be used to assess the efficacy of preparations other than pentoxifylline.
References 1. Armstrong Jr M, Kunar DR, Cummings CW. Effect of pentoxifylline on myocutaneous flap viability in pigs. Otolaryngol Head Neck Surg 1993;109:668—75. 2. Bekerecioglu M, Kutluhan A, Demirtas I, et al. Prevention of adriamycin-induced skin necrosis with various free radical scavengers. Surg Res 1998;75:61—5. 3. Cram AE, Chang P. Clinical applications of free skin grafts. In: Janusz Bardach, editor. Local flaps and free skin grafts. St. Louis: Mosby; 1992. p. 157. 4. Fabia R, Travis DL, Levy MF, et al. Effect of pentoxifylline on hepatic ischemia and reperfusion injury. Surgery 1997;121: 520—5. 5. Hidalgo DA. Lower extremity avulsion injuries. Clin Plast Surg 1986;13:701—10. 6. Musgrave RH, Lehman JA. Composite grafts. In: Georgiade G, Georgiade NG, Riefkohl R, Barwick WJ, editors. Textbook of plastic, maxillofacial and reconstructive surgery. Baltimore: Williams and Wilkins; 1992. p. 47. 7. National Pressure Ulcer Advisory Panel. Pressure ulcers prevalence, cost and risk assessment: consensus development conference statement. Decubitus 1989;2:24—8. 8. Russel TA. General principles of fracture treatment. In: Crenshaw AH, editor. Campbell’s operative orthopaedics. St. Louis: Mosby; 1992. p. 725—84. 9. Savas C, Dindar H, Bilgehan A, et al. Pentoxifylline attenuates reperfusion injury in testicular torsion. Scand J Urol Nephrol 2002;36:65—70. 10. Urbaniak JR, Evans JP, Bright DS. Microvascular management of ring avulsion injuries. J Hand Surg 1981;6A:25—30. 11. Yessenow RS, Maves MD. The effects of pentoxifylline on random skin flap survival. Arch Otolaryngol Head Neck Surg 1989;115:179—81.
www.elsevier.com/locate/injury
The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study Volkan Oztuna a,*, Metin M. Eskandari a, Sakir Unal b, Mehmet Colak a, Tuba Karabacak c a
Department of Orthopaedics, Mersin University School of Medicine, Ihsaniye Mah, 4935 Sokak No. 3, 33079 Mersin, Turkey b Department of Plastic and Reconstructive Surgery, Mersin University School of Medicine, Turkey c Department of Pathology, Mersin University School of Medicine, Turkey Accepted 20 February 2006
KEYWORDS Pentoxifylline; Skin; Degloving injury
Summary Background: Management of skin degloving injuries is still a problematic issue and the avulsed part of the skin may become necrotic. In this pilot study, we attempted to develop an experimental model for degloving injuries and investigated the efficacy of pentoxifylline, a well-known potent agent in enhancement of erythrocyte flexibility and tissue vascularization, in treatment of this injury model. Methods: Degloving injuries were created in 15 rats’ tails by circular puncturing of the skin at the middle of the tail and then applying moderate force to avulse the skin from the underlying tissue. Then, the skin was repaired back to its original position. No treatment was given in the first group (n = 6). In the second group (n = 3), 0.4 cm3 physiological serum was administered intraperitoneally for 10 days. In the third group (n = 6), intraperitoneal 25 mg/kg pentoxifylline was administered for 10 days. Tails were observed daily for 21 days and then examined histopathologically. Results: At the end of the study, the avulsed segment of the skin became cyanotic and ulcerated in the first and the second group, and in the third group, the skin was intact. In histopathological examination, loss of superficial ephitelium and dense infiltration of inflammatory cells were seen in groups 1 and 2, and the skin layers were normal in the group 3. Conclusion: Pentoxifylline improved tissue preservation and was proved to be highly beneficial in treatment of skin degloving injuries. # 2006 Elsevier Ltd. All rights reserved.
* Corresponding author at: Viransehir Mah. Moda Plaza, C blok, D: 10, Mersin 33190, Turkey. Tel.: +90 324 3374300x1161; fax: +90 324 3374305. E-mail address: [email protected] (V. Oztuna). 0020–1383/$ — see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2006.02.025
The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study
639
Introduction In skin avulsion injuries, as the subcutaneous vascular plexus is severed, the blood supply of the avulsed segment of the skin can be damaged. Attempts at suturing the skin back to its original position may lead to necrosis.5 Avulsed skin, in fact, constitutes a composite graft which includes the skin and the subcutaneous tissue. It is believed that survival of the graft depends on early establishment of circulation by direct vessel-to-vessel anastomosis between the graft and the recipient bed.6 In this condition, a pharmacological agent having the capability to improve the vascularisation is necessary. Pentoxifylline is a well-known potent agent in enhancement of tissue vascularisation due to its ability to increase red blood cell flexibility and improves the flow properties of blood by decreasing its viscosity.1,4 In this pilot study, we designed an experimental model for skin degloving injury and examine the efficacy of pentoxifylline in treatment of this injury model.
Materials and methods We used 15 male Spraque—Dawley male rats with a body-weight of between 230 and 300 g. The study began after permission was obtained from the Institutional Animal Research Council. The subjects were anaesthetised by an intramuscular injection of 50 mg/kg ketamine hydrochloride (Ketalar1; EWL Eczacıbas¸ı Warner Lambert Istanbul, Turkey). The injury was created by circular puncturing of the skin in the middle of the tail with an scalpel No. 11 and then applying moderate force distally to avulse the skin and subcutaneous tissue from the underlying tendinous and vascular tissue. The skin was separated in approximately 3 cm length but still attached to the distal tail (Fig. 1). Fifteen minutes after the injury, the skin was repaired with 4/0 vicryl. The first group (n = 6) was taken as the control group. In the second group (n = 3), 0.4 cm3 physiological serum (the same volume of liquid used in the third group) was administered intraperitoneally for 10 days to examine the possible therapeutic effect of fluid injection in terms of volumetric replacement. In the third group, 25 mg/kg (0.4 cm3) pentoxifylline (Trental, Aventis, USA), was administered intraperitoneally after repair, and then 25 mg/kg/day for 10 days. The colour of the skin and the status of the wound were observed daily for 21 days. At the end of the third week, tails were examined histopathologically.
Figure 1
Injury model: avulsion of the skin in rat’s tail.
Results In the first 2 days, all the tails were swollen and the avulsed segments of the skin were cyanotic and oedematous. After the third day, progressive deterioration in the colour of the avulsed segment of the skin was observed in the groups 1 and 2. On the 21st day, the boundary of the necrosis in groups 1 and 2 was approximately 3 cm in length in the avulsed segment of the skin. The distal part of the tail was still edematous (Fig. 2). In group 3, cyanosis and oedema disappeared after the third day and there was no necrotic area in the tails at the end of the study (Fig. 3). No wound infection occurred in the tails. In histopathological examination, the specimens were fixed in 10% formalin for 24 h and standard dehydration and parafin wax embedding procedures were used. Haematoxylin and eosin-stained slides were prepared by using standard methods. Skin lesions were classified by using the National Pressure Ulcer Advisory Panel (NPUAP)7 and staged from 0 to 4 according to following criteria–—Stage 0: normal skin; Stage I: non-blanchable erythema (inflammation) of intact skin the heralding lesion of skin ulceration; Stage 2: partial thickness skin lost involving epidermis, dermis, or both; Stage 3: full
640
V. Oztuna et al.
Figure 2 Necrotic segment of the skin of the tail in the groups 1 and 2.
Figure 5
Intact epidermis in the group 3 (H + E, 100).
thickness skin lost involving necrosis of subcutaneous tissue that may extend down to, but not through underlying fascia; Stage 4: full thickness skin lost with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures (e.g., tendon, joint capsule). Microscopically, in the groups 1 and 2 ulceration, loss of epidermis and superficial dermis and capillary proliferation was observed (Stage 2) (Fig. 4). The epidermis recovered its normal thickness and had no inflammation in the group 3 (stage 0) (Fig. 5).
Discussion Figure 3 group 3.
The skin was intact at the end of the study in
Figure 4 Ulceration and neutrophil accumulation in the groups 1 and 2 (H + E, 100).
In this pilot study, we created a skin degloving injury model, and then investigated the efficacy of pentoxifylline in this injury model and approved its positive effect on tissue viability by clinical and histopathological assessment. In trauma centres, clinicians encounter skin degloving injuries such as ring injuries and closed skin degloving injury of the extremities resulting from high-energy trauma with or without bony injury. Especially, in case of AO-IC 3 and AO-IC 4 closed fractures (circumscribed closed degloving injury of the skin),8 failure to care the soft tissue injuries can result in serious complications ranging from delayed wound healing to massive infection. To the best of our knowledge, there is no experimental skin degloving injury model described in the literature. We created a skin avulsion injury model in rat tails of which its shape allowed us to perform a circumferential avulsion of the skin. This model resembled a type I ring injury10 and it can be used as a standard model. In types II and III ring injuries, a perfect microsurgical treatment is needed for good results. However, in type I injuries, there is no
The effect of pentoxifylline in treatment of skin degloving injuries: An experimental study specific management to protect the viability of the avulsed skin. We think that pentoxifylline can be used for this clinical scenario as it showed a protective effect on viability of the avulsed part of the skin. It may be also a potential agent for the treatment of closed skin degloving injuries of the extremities. It is believed that skin grafts can survive via formation of direct vascular anastomoses between the recipient and donor area. This process takes place before actual capillary invasion which usually takes 72 h.3 Herein, a pharmacological agent having capacity to improve the vascularisation is necessary in this critical period. As has been explained in several studies previously, pentoxifylline has multiple actions that enhance tissue survival. Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity and enhancing tissue oxygenation. The most well-known action of pentoxifylline is its ability to increase erythrocyte flexibility, allowing easier vascularisation.1,4,11 The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement are still to be defined. It has been proved that pentoxifylline enhances the blood flow in a testicular torsion model.9 It prevents the formation of skin necrosis resulting from infiltration of antitumor agents into subcutaneous tissues2 and enhances the flap survival in humans.1,11 In our study, pentoxifylline showed a protective effect on viability of the avulsed part of the skin. We think that in the first 72 h after injury, pentoxifylline improved erythrocyte flexibility and eased the formation of direct vascular anastomoses between the recipient and the donor area. It is evident from this study that pentoxifylline therapy resulted in significant improvement in
641
the degree of tissue preservation and proved to be highly beneficial in treatment of skin degloving injury model in rats. This experimental model may serve a standard technique that can be used to assess the efficacy of preparations other than pentoxifylline.
References 1. Armstrong Jr M, Kunar DR, Cummings CW. Effect of pentoxifylline on myocutaneous flap viability in pigs. Otolaryngol Head Neck Surg 1993;109:668—75. 2. Bekerecioglu M, Kutluhan A, Demirtas I, et al. Prevention of adriamycin-induced skin necrosis with various free radical scavengers. Surg Res 1998;75:61—5. 3. Cram AE, Chang P. Clinical applications of free skin grafts. In: Janusz Bardach, editor. Local flaps and free skin grafts. St. Louis: Mosby; 1992. p. 157. 4. Fabia R, Travis DL, Levy MF, et al. Effect of pentoxifylline on hepatic ischemia and reperfusion injury. Surgery 1997;121: 520—5. 5. Hidalgo DA. Lower extremity avulsion injuries. Clin Plast Surg 1986;13:701—10. 6. Musgrave RH, Lehman JA. Composite grafts. In: Georgiade G, Georgiade NG, Riefkohl R, Barwick WJ, editors. Textbook of plastic, maxillofacial and reconstructive surgery. Baltimore: Williams and Wilkins; 1992. p. 47. 7. National Pressure Ulcer Advisory Panel. Pressure ulcers prevalence, cost and risk assessment: consensus development conference statement. Decubitus 1989;2:24—8. 8. Russel TA. General principles of fracture treatment. In: Crenshaw AH, editor. Campbell’s operative orthopaedics. St. Louis: Mosby; 1992. p. 725—84. 9. Savas C, Dindar H, Bilgehan A, et al. Pentoxifylline attenuates reperfusion injury in testicular torsion. Scand J Urol Nephrol 2002;36:65—70. 10. Urbaniak JR, Evans JP, Bright DS. Microvascular management of ring avulsion injuries. J Hand Surg 1981;6A:25—30. 11. Yessenow RS, Maves MD. The effects of pentoxifylline on random skin flap survival. Arch Otolaryngol Head Neck Surg 1989;115:179—81.