Improved ischemic island skin flap survival with continuous intraarterial infusion of adenosine triphosphate--magnesium chloride and superoxide dismutase: a rat model

Neurovascular island skin flaps are still hampered by occasional necrosis of their most distal aspect. Cells subjected to prolonged hypoxic conditions become intracellularly depleted of needed metabolic substrates and eventually die. Once hypoxic conditions are improved, ischemic tissue suffers further injury from the rapid accumulation of oxygen free radicals. This study showed 53% survival of a standard random flap constructed on the inferior epigastric neurovascular bundle of a rat. Random flap survival increased to 65% after intraarterial infusion of adenosine triphosphate--magnesium chloride (ATP-MgCl2); to 75% after superoxide dismutase infusion; and to 98% after combined ATP-MgCl2 and superoxide dismutase infusion. Neither substrate appeared to act by increasing blood flow to the ischemic tissue.     

The effects of streptokinase on ischemic flaps

Prolonged ischemic periods may inhibit success in microsurgical procedures. Impairment of fibrinolytic activity could be a factor contributing to this problem. Ischemic epigastric flaps in the rat were used as a model to measure the potential of streptokinase to improve blood flow and tissue survival. A moderate but statistically significant improvement in flap survival was observed and is felt to be due to the enhancement of fibrinolytic activity previously impaired by ischemia. Saline irrigation alone in control animals was found to be detrimental to flap survival. Streptokinase might prove beneficial when dealing with an ischemic replant or free flap.     

Experience with calcium antagonists nitrendipine, diltiazem, and verapamil and beta 2-agonist salbutamol in salvaging ischemic skin flaps in rabbits

This study investigated the efficacy of selected agents in the salvage of experimental skin flaps in rabbits after 21 hours of 25 degrees C ischemia. Calcium channel antagonists nitrendipine, diltiazem, and verapamil increased ischemic skin flap survival in rabbits from 33.3% for buffered saline infused controls to 71.4% (P less than 0.05), 71.4% (P less than 0.05), and 50.0% (not significant) respectively. The beta 2-adrenoceptor agonist salbutamol produced an increase in survival to 64.3%, which narrowly missed statistical significance. All four test agents invoked a vasodilatory response (greatest for nitrendipine, diltiazem, and salbutamol), a slight fall in blood pressure, and a small increase in heart rate. It is concluded that the vasodilatory response in the microcirculation of the ischemic flap helped to minimize the risk of occlusion due to thrombosis or cell sludging during reperfusion, thus leading to improved flap survival.     

Effect of superoxide dismutase for improvement of survival of ischemic reperfused island skin flap]

Using a rat model, we evaluated the effect of SOD on the survival of ischemic reperfused island skin flaps. In experiment 1, the oxygen free radical concentration in the flaps was measured by the technique of ESR. The results showed that the oxygen free radical concentration in ischemic reperfused flaps was significantly higher than in the corresponding control flaps (P less than 0.001). In experiment 2, the flaps were perfused with SOD (2000 U in 1 ml saline) before reperfusion after 8 hours of ischemia. Seven days after operation, the area of flap survived in the test group was significantly larger than in the control group (P less than 0.0005). The obtained data demonstrated that the generation of oxygen free radical increases with time during ischemia reperfusion in island skin flap and the role of oxygen free radical in tissue injury following ischemia and reperfusion. The use of SOD can enhance the survival of ischemic island skin flap.     

Review of postoperative pharmacological infusions in ischemic skin flaps

No single drug has yet been found which can overcome the inflammatory and microvascular changes which occur in a skin flap after ischemia-reperfusion. Nevertheless, the continued failure of approximately 7% of all free flap transfers clinically suggests that there may be a place for pharmacological intervention at the time of threatened flap failure. To date, plastic and reconstructive microsurgeons have been reluctant to use drugs because of the mass of conflicting evidence emanating from the plastic surgery literature. However, scientists and surgeons now have a clearer understanding of the problems arising in ischemia-reperfusion. Multi-acting drugs which can inhibit most of the important inflammatory changes would be the ideal. This review considers some of the historical developments in the pharmacological treatment of ischemic flaps in the past decade and looks to the future when pharmacological infusions may be part of the routine for salvaging failing skin flaps. © 1994 Wiley-Liss, Inc.     

腓骨复合瓣游离移植修复下颌骨缺损

目的　总结应用游离腓骨复合瓣修复下颌骨缺损的经验。方法　 1999年 6月～ 2 0 0 0年 11月对5 8例应用腓骨复合瓣游离移植修复下颌骨缺损的病例作回顾性研究 ,其中男 37例 ,女 2 1例。年龄 12～ 6 5岁 ,平均4 0 .9岁。分析下颌骨缺损原因 ,分析腓骨瓣设计、受区血管、组织瓣成活情况及术后并发症的发生情况。结果　 5 8例中 5 2例为肿瘤切除术后修复 ,其中 4 3例为一期修复 ,9例为二期修复。采用游离腓骨复合骨瓣的腓骨长度 4～2 1cm ,平均 11.4 cm ;腓骨的截骨为 1～ 4次数 ,平均 2 .1次 ;骨瓣带皮岛最大范围 12 cm× 8cm,最小 3.0 cm×1.5 cm。术后游离腓骨瓣的临床成功率为 96 .6 % (5 6 /5 8) ,失败 2例。受供区并发症主要为血肿、积液、创口感染和腺瘘 ,有 4例为植皮坏死和创口感染 ,发生率为 2 4 .1% ,但不影响效果。结论　游离腓骨瓣在修复下颌骨缺损中具有操作灵活 ,安全可靠 ,制备简便 ,并发症少 ,可以满足各种类型下颌骨缺损修复的需要     

Postischemic flap washout with hydroxyethyl starch (HAES) and its beneficial effect on the no-reflow phenomenon in rat skin island flaps

This study investigated the possible effect of hydroxyethyl starch (HAES) as a postischemic perfusion washout on survival of skin flaps. Forty-eight, male, Sprague-Dawley rats were used in this experiment. A 4×6 cm unilateral island skin flap based on the superficial inferior epigastric artery and vein was raised. The femoral neurovascular bundle supplying the flap pedicle was also dissected free. The flaps were divided into four groups, each consisting of 12 rats. Group 1 (Nonishemic control); Group 2 (Control) – no perfusion washout; Group 3 (Saline) – postischemic washout with normal saline solution; Group 4 (HAES) – postischemic washout with hydroxyethyl starch 10% (HAES) solution. The flaps were subjected to 11 hours of warm ischemia. Thirty minutes prior to the completion of the ischemic period, the flaps were perfused with normal saline solution in group 3 and with HAES in group 4. The percentage of flap survival was assessed on postoperative day 7. Statistical analysis was performed using the Student’s t-test. Flap survival rates for Group 4 (HAES) were significantly greater than Group 2 (Control nonperfusion washout) and Group 3 (saline solution) (p<0.001). This is the first study to investigate the effect of HAES on skin flap survival based on the results, HAES solution may be useful in clinical practice. Received: 6 August 1997 / Accepted: 11 December 1997     

The effects of hyperbaric oxygen on free flaps in rats

The effects of hyperbaric oxygen on survival were investigated in free flaps and island flaps. Skin flaps transplanted following 18, 21, and 24 hours of preservation at 24 degrees C demonstrated survival rates of 20%, 10%, and 0%, respectively. Treatment with hyperbaric 100% oxygen improved the survival rates to 66%, 67%, and 40%. A preservation time of 21 to 24 hours at room temperature appears to be the threshold of irreversible ischemic damage. In acute island flaps, flap survival was improved significantly from 35% to 53% and 64% of the random flap area by preoperative or postoperative treatment, respectively. Prolonged preoperative and postoperative treatment improved survival to 66%.     

A biochemical study of acute ischemia in rodent skin free flaps with and without prior elevation

Elevation of a vascular island flap 24 hours before an ischemic insult (prior elevation) has been shown to significantly increase flap survival, and to decrease blood thromboxane levels, compared with acutely ischemic flaps. The current study considered whether prior elevation causes other biochemical alterations that could be beneficial for flap survival. Tissue levels of adenosine triphosphate (a major tissue energy store), superoxide dismutase (a major defense against free radicals), xanthine oxidase (an enzymatic source of free radicals), and edema were measured. Rat epigastric flaps, with or without prior elevation, had 10 or 12 hours of acute ischemia. Biopsies were taken at 0, 12, or 24 hours after reperfusion. Skin from flaps with no ischemia (control flaps) or control skin was harvested at the same times. Acutely ischemic flaps had significantly lower levels of adenosine triphosphate and less edema than those in prior elevated ischemic flaps after 12 hours of ischemia (both, p less than 0.05). Superoxide dismutase and xanthine oxidase did not vary significantly. It is not clear whether the increased adenosine triphosphate level in prior elevated flaps is the cause or the result of increased tissue viability. Prior elevation did not alter free radical mechanisms. Furthermore, prior elevation was beneficial for flap survival despite increased edema.     

皮肤软组织深度损伤的外科治疗

目的 探讨皮肤软组织深度损伤的治疗方法.方法 2006年7月-2008年1月,笔者单位共收治皮肤软组织深度损伤患者56例,其中火焰烧伤23例、电击伤17例、热压伤7例、撕脱伤6例,其他原因(交通伤、挤压伤、皮肤软组织感染)致伤3例.共应用各类皮瓣65个修复创面,其中局部皮瓣21个、远位带蒂皮瓣18个、游离皮瓣26个,皮瓣面积1.5 cm×1.0 cm～39.0 cm×23.0 cm.结果 60个皮瓣完全成活,3个部分坏死,2个完全坏死.局部皮瓣成活率为95.2%,远位带蒂皮瓣成活率为88.9%,游离皮瓣成活率为92.3%.各类皮瓣成活率比较,差异无统计学意义(P>0.05).结论 皮瓣移植仍然是修复深度皮肤软组织损伤的有效方法,在保证成活率的前提下,采用游离皮瓣进行修复具有一定的优越性.     

Factors involved in salvaging ischaemic rabbit skin flaps: ATP and free radicals but not thromboxane

Rabbit epigastric free flaps were subjected to ischaemia at 25 degrees C for 24 hours. At the time of revascularisation the flaps were infused intra-arterially with one of the following: Hanks balanced salt solution (control), the high energy phosphates PEP/ATP, the thromboxane synthetase inhibitor dazoxiben hydrochloride, the free radical scavenger SOD and a combination of all these agents (treated groups). Control ischaemic flap survival at post-ischaemia day 7 was 23.5%, while the other treatments resulted in improved flap survival of 43.5% (p less than 0.025), 23.5% (not significant), 38.6% (p less than 0.05) and 35.7% (p less than 0.05) respectively. None of these agents improved post-ischaemic blood flow significantly. These results would support the use of PEP/ATP or SOD in the clinical treatment of failing ischaemic skin flaps but do not support the use of dazoxiben hydrochloride.     

Vascular endothelial growth factor (VEGF) expression and the effect of exogenous VEGF on survival of a random flap in the rat.

The induction of endogenous vascular endothelial growth factor (VEGF) production in the skin flap with ischemic injury and the effect of exogenous VEGF on survival of the ischemic skin flap were studied in rats. A dorsal flap model (3x10 cm(2)) was used in this study. In Part I, biopsies were taken from the flap at 2.5, 5.5, and 8.5 cm distances from the distal edge at 0, 6, 12, and 24 h after the flaps were sutured. Malonyldialdehyde (MDA) and VEGF(165) protein level were measured. In Part II, exogenous VEGF (1 microg/ml) was injected subdermally into the flaps in 14 rats before the flaps were replaced. Flaps that received a saline injection were used as the controls. The skin paddle survival was measured on postoperative day five. The results showed that the MDA level in the distal part of the flap significantly increased at 24 h postoperatively when compared to MDA in other parts of the flap. However, VEGF levels in the distal part of the flap significantly decreased when compared to the middle part of the flap. Subdermal injection of exogenous VEGF to the distal area of the flap could significantly improve survival of the distal flap (89% of total skin paddle) when compared to the control, which had a 64% mean percent survival. We conclude that production of endogenous VEGF protein is significantly increased in the skin flap with mild ischemia, but decreased in the flap with severe ischemia. Administration of exogenous VEGF could significantly enhance survival of ischemic flaps.     

Salutary effects of radiopaque contrast media on the survival of random-pattern skin flaps in the rat: an experimental study

The radiopaque contrast medium diatrizoate, has a vasodilator effect so that it is used in sudden-deafness secondary ischemic injury. However, ischemic problems are encountered, especially when longer flaps are elevated. A longer flap also has ischemic and relatively ischemic tissue, and may obtain some benefit from contrast media. Forty male Sprague-Dawley rats, weighing about 350-400 g, were used, and randomly divided into four groups (n = 10 rats each group): group 1 was the control, group 2 the diatrizoate, group 3 the iopamidol, and group 4 the iothalamate group. A rectangular 3 x 10 cm caudally based dorsal skin flap was elevated, and sutured back to its original place. In the control group, no pharmacologic agent was administered. Sodium-meglumine-diatrizoate 10 mg/kg/day was administered parenterally in the first experimental group (diatrizoate group); iopamidol 10 mg/kg/day in the second experimental group (iopamidol group); and iothalamate sodium 10 mg/kg/day in the third experimental group (iothalamate group) for 7 postoperative days. On postoperative day 7, all flaps were photographed, and the area of flap survival was measured by using a polar planimeter. The results were statistically evaluated with the Kruskal-Wallis test and Mann-Whitney U-test (P = 0.05). The mean flap survival ranged from 79% in the iopamidol group to 83% in the diatrizoate group, and was significantly greater in all experimental groups (P < 0.05) compared to the control group (59%). There was no significant difference between experimental groups (P < 0.05). We believe that radiopaque contrast media have a beneficial effect in improving skin flap viability when distal flap necrosis is a potential complication of longer flaps.     

The effect of a free-radical scavenger, N-2-mercaptopropionylglycine, on the survival of skin flaps

Oxygen free radicals may have an important role in tissue injury, which occurs on reperfusion of previously ischemic skin flaps. Therefore, therapy directed against the toxic effects of reactive oxygen species may protect skin flaps from ischemia/reperfusion injury. Various scavengers of oxygen free radicals have previously been reported to be effective in ameliorating ischemia/reperfusion injury. In the present study, N-2-mercaptopropionylglycine (MPG), a free-radical scavenger, was evaluated for its effectiveness in limiting the extent of necrosis resulting from ischemia/reperfusion injury in rat skin. Island skin flaps were elevated in the abdomen and groin based on an inferior epigastric neurovascular pedicle. The venous drainage from the flap was occluded for 7 hours, and reperfusion was established. The majority of flaps in the control group exhibited complete necrosis on Day 7 postoperatively. Treatment with systemic MPG (20 mg/kg of body weight) significantly improved flap survival from 22 to 71% (p less than 0.01) when administered at the time of reperfusion. However, MPG administered 1 hour after reperfusion did not influence the survival of the flaps. The results suggest that MPG may exert its beneficial effects on flap survival by scavenging oxygen free radicals formed at the time of reperfusion following prolonged ischemia.     

Effect of scavengers of superoxide radicals in reducing ischemic injury of skin flaps

In recent years, an extensive attention has been paid to the effects of oxygen free radicals on tissue injury. Although some studies have been demonstrated that the oxygen free radicals are implicated in the pathogenesis of ischemic injury in island skin flaps, none of the experimental study has been domestically reported. The authors used the island flap of the rats as an animal model to investigate the effectiveness of free radical scavengers in preventing reperfusion injury after ischemia in island skin flap. The results suggest that the scavenger of superoxide radical--superoxide dismutase (SOD) which was directly injected into the flap before and after reperfusion increases the survival rate of the flap obviously (93.6% v.s. control 63.7%). This findings are consistent with the theory that the ischemic tissue injury is caused by the oxygen free radicals produced at the time of tissue reperfusion.     

Thrombolytic therapy: what is its role in free flap salvage?

Thrombolytic agents have been demonstrated to improve free flap salvage in animal models. However, clinical evidence regarding their efficacy has been scant. The authors reviewed their experience with flap salvage using thrombolytic therapy in 1,733 free flaps from February 1990 to July 1998. Patients with intraoperative pedicle thrombosis were excluded from this review. Forty-one of the 55 free flaps that were reexplored emergently were identified as having pedicle thrombosis. Of these 41 flaps, 28 free flaps were salvaged (flap salvage group, 68%) and 13 free flaps failed (flap failure group, 32%). Thrombolytic therapy (urokinase in 7 patients, tissue plasminogen activator in 1 patient) was used in six flaps in the flap salvage group and two flaps in the flap failure group. Statistical analysis demonstrated no difference between the two groups with regard to thrombolytic therapy. There was also no difference between the two groups with regard to use of systemic heparin (100-500 U per hour) at the time of pedicle thrombosis or with regard to whether Fogarty catheters were used. Smoking, preoperative radiotherapy, and the use of interpositional vein grafts during initial flap reconstruction had no impact on the outcome of flap salvage. The flap salvage group was reexplored at a mean of 1.5 days compared with the flap failure group, which was reexplored at a mean of 4.2 days (p = 0.007). Early detection of pedicle thrombosis remains the most important factor in the salvage of free flaps. Although these numbers are small and definitive statements cannot be made, the role of thrombolytic agents in free flap salvage requires further clinical evaluation.     

Aprotinin in Ischemia-Reperfusion injury: Flap survival and neutrophil response in a rat skin flap model

Multiple drugs have been used in experimental skin flap models to reduce the effects of reperfusion ischemia. The effects of antiproteases, however, have not been studied. A skin flap ischemia reperfusion model was developed in the rat to study the effects that aprotinin, a broad-spectrum antiserine protease, would have on skin flap viability. Thirty-two male rats underwent elevation of a ventral pedicled skin flap based on the superficial inferior epigastric artery. The flaps were subjected to 10 hr of warm ischemia by clamping the neurovascular pedicle followed by reperfusion. Aprotinin or saline (control) was administered systemically via the contralateral femoral vein either before or after the ischemic insult. Full-thickness skin biopsies were obtained at 1, 8, and 24 hr into reperfusion. Biopsies were evaluated for neutrophil concentration (using a myeloperoxidase [MPO] assay) and thromboxane B₂ [TxB₂] content. Flap survival was calculated at 1 week using standardized photography and computer-assisted digital imaging. Aprotinin given before an ischemic insult significantly improved flap survival compared to saline controls (52.3% alive vs. 29.6%, P = 0.0132, unpaired t-test). Aprotinin given after ischemia did not significantly influence flap survival (28.8% vs. 34.4% in saline controls, P = 0.708). MPO levels in the aprotinin preischemia treatment group were significantly less at 1 and 8 hr into reperfusion, indicating decreased neutrophil numbers. No statistical difference in TxB₂ levels was noted in either group at any time after reperfusion. Aprotinin significantly improves skin flap survival when given prior to but not after an ischemic insult. Aprotinin appears to lower the concentration of neutrophils in skin flaps pretreated with the drug. Reperfused skin flap levels of thromboxane B₂ are unaffected by the pre- or postischemic administration of aprotinin. © 1998 Wiley-Liss, Inc. MICROSURGERY 18:354–361, 1998     

Customized reconstruction with the free anterolateral thigh perforator flap

From April of 2003 through September of 2006, 70 free anterolateral thigh (ALT) flaps were transferred for reconstructing soft-tissue defects. The overall success rate was 96%. Among 70 free ALT flaps, 11 were elevated as cutaneous ALT septocutaneous vessel flaps. Fifty-seven were harvested as cutaneous ALT myocutaneous "true" perforator flaps. Two flaps were used as fasciocutaneous perforator flaps based on independent skin vessels. Fifty-four ALT flaps were used for lower extremity reconstruction, 11 flaps were used for upper extremity reconstruction, 3 flaps were used for trunk reconstruction, and 1 flap was used for head and neck reconstruction. Total flap failure occurred in 3 patients (4.28% of the flaps), and partial failure occurred in 5 patients (7.14% of the flaps). The three flaps that failed completely were reconstructed with a free radial forearm flap, a latissimus dorsi flap and skin grafting, respectively. Among the five flaps that failed partially, three were reconstructed with skin grafting, one with a sural flap, and one with primary closure. The free ALT flap has become the workhorse for covering defects in most clinical situations in our center. It is a reliable flap with consistent anatomy and a long, constant pedicle diameter. Its versatility, in which thickness and volume can be adjusted, leads to a perfect match for customized reconstruction of complex defects.     

Improved survival in free skin flap transfers in rats

We have demonstrated previously that oxygen-derived free radicals are important mediators of tissue injury in experimental island skin flaps that have been subjected to prolonged ischemia (vascular occlusion) followed by reperfusion. In this study the role of oxygen free radicals in ischemia/reperfusion injury has been investigated in free flap transfers. Groin skin flaps were harvested, stored at room temperature for 21 to 24 hours, and transplanted to the contralateral groin. These free flap transfers normally exhibit a high incidence of complete necrosis. Treatment before the onset of reperfusion with a single dose of superoxide dismutase (SOD), a scavenger of superoxide radicals, increased the survival rate of these skin flaps from 38% in the control group to 76% (p less than 0.025). Tissue levels of SOD were measured before ischemia, after ischemia but before reperfusion, and 30 minutes after reperfusion: untreated flap tissues, which were destined to undergo necrosis, exhibited a significant decrease in SOD activity after reperfusion, whereas SOD-treated flap tissues, destined to survive, demonstrated increased enzyme activity. High levels of tissue SOD activity thus appeared to be associated with improved flap survival. The results have significant clinical implications with regard to organ preservation and transplantation.     

The role of metal ions in ischemia/reperfusion injury in skin flaps

The role of hydroxyl radical generation by the metal-catalyzed Haber-Weiss reaction in producing injury to postischemic skin flaps in rats was evaluated. The venous drainage from groin island flaps was occluded for 7 hr and then reperfused. The flaps were infused with either deferoxamine, CaNa2EDTA, histidine, salicylate, or vehicle (saline) at the time of reperfusion. In another experimental group, the role of hydrogen peroxide was evaluated by the infusion of catalase at the time of reperfusion. Treatment with a single dose of deferoxamine (40 mg/kg), CaNa2EDTA (50 mg/kg), or histidine (50 mg/kg), significantly increased the flap survival rate from 24 to 63, 75, and 63%, respectively. A large dose of salicylate (80 mg/kg) improved the flap survival rate (to 63%): a smaller dose (40 mg/kg) offered no improvement. A large dose of catalase ameliorated the survival rate (to 88%). The results suggest that the presence of metal ions is required for the expression of free radical-induced tissue damage. Hydrogen peroxide appears to be essential for the production of this injury.