Abstract
Flap necrosis is still a significant complication in all types of flap surgery. The effect of parenteral pentoxifylline and nitroglycerin in improving survival of ischemic skin flaps was tested in Wistar rats. In the control group (n = 15) the mean viable length of the flaps was calculated to be 6.160 ± 0.936, and non-necrotic flap area was found to be 1859.1 ± 269.3. In the group treated with pentoxifylline and nitro-glycerin (n = 15), the mean viable length of the flap was calculated to be 6.907 ± 0.617, and the mean nonnecrotic flap area was found to be 2078.5 ± 172.7. In this study results showed that the use of parenteral pentoxifylline and topical nitroglycerin is effective on skin flap survival.
Partial flap necrosis in distal random skin flaps continues to be a significant surgical complication. A major factor influencing the development of necrosis in the distal end of skin flaps is the inadequacy of nutrient blood flow, probably caused by arterial insufficiency, which leads to ischemic necrosis. 1 Many forms of therapy have been used to enhance tissue survival in random-pattern skin flaps. Most have focused on improving tissue blood flow and oxygenation, decreasing tissue metabolic needs, or blocking reperfusion-induced ischemic injury. 2 – 4
No standard drug currently in use has been consistently effective in preserving peripheral vascular circulation and thereby enhancing the survival of skin flaps. Pentoxifylline is a rheologic agent that reduces platelet aggregation, reduces fibrinogen levels, and produces a mild vasodilating effect. However, the major rheologic effect of pentoxifylline is thought to be mediated by increased erythrocyte flexibility. 5 This experimental study was undertaken to determine the effect of topical nitroglycerin and parenteral pentoxifylline on the viability of ischemic skin flaps.
METHODS AND MATERIAL
In this study 30 Wistar rats weighing between 120 and 160 gm were used. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals (NIH publication no. 85–23, revised 1985). They were housed under standardized environmental conditions, with free access to food and water. They were divided into two groups, and they received the following treatment.
In group 1 (pentoxifylline ± nitroglycerin) pentoxifylline diluted in serum saline solution (25 mg/kg/day) was injected intraperitoneally immediately after the operation. Injections were continued daily for 7 days, and 25 mg topical nitroglycerin was applied at the same time. In group 2 (control) animals were injected intraperitoneally with the same volume of saline solution after the operation.
All animals were anesthetized by subcutaneous administration of sodium pentobarbital at a dose of 30 mg/kg. Dorsal hair was removed with electric clippers, and the rats were placed in a standard position with limbs outstretched. A 3 × 9 cm caudally based, dorsal midline flap was raised to level just below the panniculus carnosus. No special effort was taken for hemostasis, and the flap was sutured back into place with continuous 4–0 silk. In all groups each animal was kept in a different cage. Seven days after the procedure, flap survival was assessed. The surviving areas and necrotic area were drawn on acetate sheeting (Fig. 1).
RESULTS
Results are shown in Table 1. The length of the viable flap and a measurement of the flap area in millimeters were used. The necrotic area drawn on acetate paper was calculated, and flap survival was determined in square millimeters. In the control group (n = 15) the mean viable length of the flaps was calculated to be 6.160 ± 0.936, and nonnecrotic flap area was found to be 1859.1 ± 269.3. In the pentoxifylline and nitroglycerin-treated group (n = 15), the mean viable length of the flap was calculated to be 6.907 ± 0.617, and the mean nonnecrotic flap area was found to be 2078.5 ± 172.7. Student's t test was applied to the statistical analysis of independent samples, comparing the control group with the pentoxifylline and nitroglycerin group. Significant difference was found. Pentoxifylline and nitroglycerin had a significant beneficial effect on length of viable flap (p = 0.05) and nonnecrotic flap area (p = 0.05).
Length of viable flap versus nonnecrotic flap area
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Mean: 6.160 ± 0.936, 6.907 ±0.617, 1859.1 ±268.3, 2078.5 ± 172.7. Student's t test: p = 0.05 for both flap length and flap area.
DISCUSSION
There are many reports on agents used to improve the survival of flaps. In this study the effectiveness of the use of pentoxifylline and nitroglycerin have been explored. Pentoxifylline has rheologic properties that improve skin perfusion and oxygenation. 3 , 5
In the literature the studies using different animal models with various dosages and administration methods have led to noncorrelating results in relation to the effect of pentoxifylline on skin flap viability. Initial studies in the rat skin flap model suggested that administration of pentoxifylline after flap elevation enhanced flap viability. 3 , 6 , 7 Monteiro et al. 8 have used pentoxifylline by an enteral route on a 3 × 9 cm flap in rats. In their study, an increase in the flap viability was shown. 8 In our study we used Monteiro's flap, but we used pentoxifylline intraperitoneally and nitroglycerin topically. In the pig model Hodgson et al. 9 found no benefit in skin flap survival after administration of pentoxifylline for 7 days after skin flap elevation.
In our study there was statistically significant improvement in random skin flap survival after 7 days with the use of pentoxifylline and topical nitroglycerin. Our results indicate that nitroglycerin, a direct vasodilator and smooth muscle relaxant agent, and pentoxifylline, a hemorheologic agent, will enhance random skin flap survival in the rat model, if this combination is continued for at least 7 days. The effect of pentoxifylline on fibrinogen concentration, on vasodilation by release of prostacyclin, and on activation of leukocytes could be responsible for flap survival. Pentoxifylline increases erythrocyte flexibility without affecting the coagulation profile and decreases platelet aggregation. These properties are effective on ischemic skin flap survival in the rat model. Nitroglycerin is a direct vasodilator (arterial and venous).
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A, Random skin flap survival from the group of untreated control rats 7 days after surgery.
Rohrich et al. 10 examined the effect of nitroglycerin ointment on skin flap survival using both rat and pig models. This drug was chosen because of its vasodilator and smooth muscle–relaxant properties and because it may induce endothelial cells to synthesize prostacyclin, a vasodilator and inhibitor of platelet aggregation. These authors found a significant increase in survival of the axial flap with significant correlation to plasma nitroglycerin levels. However, a later study by Nichter et al. 11 failed to demonstrate enhancement of flap survival in a rat model using preoperative or postoperative topical nitroglycerin. They concluded that the difference stemmed from the fact that the flaps in the previous study were axial, whereas those used in their study were random skin flaps.
In this study our aim was to determine the effect of pentoxifylline and nitroglycerin on skin flap viability. Our results showed that parenteral pentoxifylline and topical nitroglycerin therapy are effective on skin flap survival in the rat model.
Despite improved understanding of skin flap blood supply and better flap design, failure of flaps remains a clinical problem. We believe that parenteral pentoxifylline and topical nitroglycerin may be use clinically to improve skin flap survival.