Prevention of adriamycin-induced full-thickness skin loss using hyaluronidase infiltration

Full-thickness skin ulceration after extravasation of the commonly used vesicant chemotherapeutic agent doxorubicin hydrochloride (Adriamycin) is a significant source of morbidity in cancer patients. Controversy exists regarding the appropriate management of this extravasation injury. Current therapy includes local hypothermia, local clysis with hyaluronidase, and surgical excision of the involved tissue. Experimental data supporting local clysis with hyaluronidase are limited despite its current use clinically. The purpose of this study was to determine the efficacy of local infiltration with heparin sodium, hyaluronidase, and saline in the prevention of extravasation ulcers in a rat model. One hundred fifty male Sprague-Dawley rats (Upjohn, Milan, Italy) weighing 240 to 260 g, anesthetized with sodium pentobarbital, were used in this study. One hundred thirty rats received a 0.3-ml subcutaneous flank injection of doxorubicin (1.5 mg/ml) followed 15 minutes later by local infiltration with saline (n = 10), 25 to 100 units of heparin (n = 30), or 2.5 to 10.0 units of hyaluronidase (n = 90). Control animals received either subcutaneous doxorubicin (n = 10) or subcutaneous saline alone (n = 10). Volumes of the infiltration solution were less than 1 ml in all groups. All animals were sacrificed at 4 weeks; presence and size of ulcers at the injection site were quantified. Statistical analysis was performed using the two-sided Fisher's exact test and Student's t test. Control rats injected with saline alone did not develop ulceration in any case. All rats injected with doxorubicin alone developed ulcers with an average size of 33 mm2. Heparin infiltration decreased ulcer rate by 20 to 40 percent and decreased ulcer size by up to 67 percent. Local infiltration with hyaluronidase decreased ulcer rate by 50 to 60 percent (p < 0.05, two-sided Fisher's exact test) and decreased ulcer size by up to 50 percent ( p < 0.05, Student's t test). In this rat extravasation injury model, local infiltration with saline, heparin, or hyaluronidase decreased ulcer size after doxorubicin extravasation. This effect may be secondary to dilution of the extravasant. Additionally, local infiltration with hyaluronidase decreased ulcer rate by at least 50 percent. The mechanism of this phenomenon presumably relates to the ability of hyaluronidase to temporarily decrease the viscosity of the hyaluronic acid component of ground substance, thus allowing greater diffusion of doxorubicin into the surrounding tissue and therefore decreasing its local concentration.