Effect of long‐term application of epinephrine on rat skin vasculature: Experimental study

Abstract

As a potent vasoconstrictor, epinephrine is used ubiquitously in plastic surgery. It is typically delivered subcutaneously in very low concentrations over a brief time interval. We are aware of no reports describing the long-term release of epinephrine as an independent agent to the soft tissues for the purpose of causing prolonged local vasoconstriction. This study was designed to address two goals: first, to investigate the effect of long-term local release of epinephrine from a drug delivery system on rat abdominal skin vasculature; secondly, to evaluate the pharmacological properties of this drug delivery system (DDS). Thirty male Sprague-Dawley rats, weighing 300-400 g, were included in the study. Animals were subdivided into two groups of 15 each. Group A (control group) and Group B (experimental group) were treated with saline and epinephrine-loaded microspheres (msps), respectively. The manufacturing process and formulation studies of the DDS are described. In vivo assays revealed a 7-day sustained release of epinephrine. After 7 days, neither residual nor supraphysiologic release of epinephrine was shown with high-performance liquid chromatography (HPLC). Histological studies with hematoxylin-eosin and periodic acid Schiff revealed a statistically significant increase in number of vessels as well as their diameter and wall thickness (P <0.05). Epinephrine release via this msp/DDS predictably induces local vasoconstriction over a time sequence known to be optimally associated with hypoxia and promotion of vascular augmentation. This model can be valuable in sustaining hemostasis during long-lasting (more than a few hours) surgical procedures by its long-acting vasoconstructive effect. The system's ability to intentionally cause vascular augmentation also bodes great potential in flap and graft surgery.

Does Sustained Epinephrine Release Trigger a Hypoxia-Neovascularization Cascade?

“…4,5 Epinephrine is used extensively in the practice of plastic surgery, principally for its potent vasoconstrictor effect on skin and subcutaneous tissue. It is applied locally for a short duration (i.e., 1 to 2 hours).…”

“…Until recently, no data were available for the long-term administration of epinephrine. 4,5 However, recent studies have demonstrated that epinephrine administered by protracted depot *These values were recorded on certain days along with mean Ϯ SD at the different intervals. Laser Doppler flowmeter measurements in tissue blood flow (in milliliters per minute per 100 g of tissue) revealed a significant difference between groups (p Ͻ 0.05) (see Fig.…”

“…Definition of drug dosage, in vitro and in vivo analyses, and release kinetics of the microsphere/drug delivery system were formulated as described in previous studies. 4,5 The amount of epinephrine used in these studies was 0.7 mg/kg. In the initial pilot study, this amount of epinephrine resulted in partial necrosis of the rabbits' ears where the microsphere/drug delivery system was injected.…”

“…Definition of drug dosage, in vitro and in vivo analyses, and release kinetics of the microsphere/drug delivery system in phosphate-buffered saline (pH, 7.4) at 37 Ϯ 0.5°C in a shaker bath were also formulated as described in previous studies. 4,5 Formed microspheres were extracted by centrifugation, and freeze-dried microsphere were stored in dark at 4°C. 4…”

“…[1][2][3] Recent data regarding the long-term local administration of epinephrine to soft tissues for the purpose of inducing prolonged vasoconstriction have yielded promising results. 4,5 In these studies, it was concluded that longterm release of epinephrine by a microsphere/ drug delivery system caused this continuous vasoconstriction. It is speculated that sustained vasoconstriction causes tissue hypoxia and subsequent neovascularization.…”