Critical Role of Phosphagens in the Energy Cascade of Cutaneous Ischemia and Protective Action of Phosphocreatine Analogues in Skin Flap Survival

A general understanding of the pivotal role of phosphocreatine (PCr) as the principal determinant of skin flap survival is now emerging. Definitive metabolic investigations using phosphorus (31P) and proton (1H) magnetic resonance spectroscopy (MRS) have established that the inability to replenish metabolically exhausted PCr reserves predictably correlates with skin flap necrosis. Furthermore, postoperative parenteral administration of PCr has been shown to augment effectively skin flap survival. We hypothesized that creatine kinase, the enzyme controlling the utilization of the high-energy phosphate component of PCr, is a critical determinant of the tolerance of a skin flap to ischemic insult. In other words, if the rate of utilization of PCr is too rapid, PCr stores will rapidly deplete, and the flap will not be able to withstand a period of ischemia. Alternatively, if the rate of dephosphorylation of PCr is reduced, survival of skin flaps during periods of ischemia could be extended. To test this hypothesis, we investigated the metabolic distribution and fate of cyclocreatine (cCr), a competent creatine analogue with a lower affinity for the creatine kinase enzyme. When administered as 1.5 percent (w/w) of the normal diet of laboratory rats, cCr accumulates in skin as the competent phosphagen, phosphocyclocreatine (PcCr). Cutaneous flaps elevated in these animals, and studied by 31P and 1H MRS, demonstrate that once depletion of PCr has occurred, PcCr continues to sustain ATP levels. This results in significant enhancement of skin flap survival (p < 0.005). These observations confirm the importance of the creatine kinase enzyme in cutaneous flap ischemia and suggest new approaches to augment skin flap survival.