We hypothesized that remote ischemic preconditioning (RIPC) is able to immediately affect cutaneous microcirculation at a potential fasciocutaneous free flap location at the anterolateral thigh (ALT-) region in a human in-vivo setting. This prospective controlled clinical study could demonstrate a significant increase of cutaneous oxygen saturation at the anterolateral thigh (ALT) skin territory, a significant increase of the cutaneous capillary blood flow as well as a statistical significant decrease of the postcapillary filling pressure as a marker of venous stasis during reperfusion phases immediately after RIPC. Therefore, our primary hypothesis was supported. These results should be discussed in detail.
In trauma and reconstructive surgery, tissue survival is paramount. In spite of tremendous progress in surgical techniques notably in reconstructive microsurgery, soft tissue still is endangered by both the lack of reoxygenation and the reoxygenation-associated inflammation due to reperfusion injury, especially in soft tissue trauma as well as in free flap failure . In order to reduce the deleterious effects of ischemia and reperfusion injury, several methods of ischemia tolerance induction were developed including sublethal ischemia, hyperthermia, hypothermia, drugs and growth factors [4, 5].
In plastic and reconstructive surgery, effects of ischemic preconditioning were also evaluated in free flap transplantation leading to a significant reduction of muscle flap necrosis supposedly by increasing the critical ischemia time of the free flap's soft tissue.
With the aim of reducing the number of additional procedures and the invasiveness of the individual preconditioning measures, remote ischemic preconditioning (RIPC) was introduced. The ameliorating effect of RIPC was attributed to regulation of endothelial protection, whereas other studies about the mechanisms of preconditioning effects on muscle and musculocutaneous flaps disclosed a decrease of capillary no-reflow, attenuation of arteriolar vasospasm and an increase of blood flow response [11, 16–18]. Furthermore, if ischemic preconditioning is applied directly before critical soft tissue ischemia, it protects both against the leukocytic inflammatory reperfusion injury and against microcirculatory dysfunction. On the other hand, ischemic preconditioning performed 24 hours or more before critical soft tissue ischemia acts anti-inflammatory, but is not capable of improving the microcirculation . The short-term microcirculatory assessment in our study was performed straight after remote ischemia to detect acute cutaneous microcirculatory effects of remote ischemic preconditioning. The intention of this study was not to evaluate the protective effects of RIPC on soft tissue in general over days after trauma or operation, but to detect whether RIPC has effects on cutaneous microcirculation and if so what kind of effects these might be. No other study before has demonstrated microcirculatory effects of RIPC on skin which should also be considered to be an important body organ that must be protected against ischemia in several settings.
Although it is generally accepted that IP increases flap survival by enhancing microvascular perfusion, the molecular and microcirculatory mechanisms are still not completely understood. The noninvasive application of a tourniquet at the hindlimb to induce IP was introduced by Kuentscher et al. and demonstrated to be as effective as the invasive clamping of the flap's pedicle itself, including both adipocutaneous and muscle flaps .
Recently, remote ischemic preconditioning demonstrated a modulation of hepatic microcirculation with consecutive reduction of the effects of ischemic reperfusion injury in an in-vivo animal model. RIPC in that setting significantly increased red blood cell velocity, sinusoidal flow and sinusoidal perfusion along with decreased neutrophil adhesion and cell death. For remote preconditioning the tourniquet was tightened around the limb until no flow was detected. The procedure involved 5 minutes of ischemia followed by 5 minutes of reperfusion. This was repeated four times . Regarding myocardial perfusion, Hooele et al. could not find an effect of RIPC on coronary microvascular resistance or coronary flow in humans . Nevertheless, Thielmann et al. found that myocardial injury after coronary artery bypass grafting was reduced by RIPC . Zimmermann et al. demonstrated RIPC as protective from acute kidney injury in patients following cardiac surgery. In that study remote ischemic preconditioning was applied by an automated thigh tourniquet consisting of three 5-minute intervals of lower extremity ischemia separated by 5-minute intervals of reperfusion. Within 48 hours after surgery there was a significant both absolute and relative risk reduction due to preconditioning . Another recent trial found no evidence that remote ischemic preconditioning provided protection of kidney function in children undergoing operation for complex congenital heart disease. Four cycles of five minutes RIPC were applied in that study .
The clinical and experimental data about RIPC in current literature remains confusing. An equal microcirculatory effect of RIPC on different kinds of tissue obviously is not mandatory demonstrated in several studies. A dose effect dependency can still not be included in RIPC because of the fact that there is still a non-equivalent effect apparent in different trials with identical dosages of RIPC. The main reason for this heterogeneous scientific data could be the indisputable heterogeneity of clinical studies concerning with RIPC, especially in terms of methodology and cohorts . Thus, basic scientific research on RIPC is mandatory and must include investigations on healthy cohorts. For this reason, we included only young, healthy subjects in our study and focused our investigation on immediate and short-term effects of RIPC on a currently scientifically non-investigated body area.
Current scientific data demonstrate that three cycles of IP are significantly superior to one or two cycles, regardless of whether the cycles were 5 min or 10 min . According to that current literature, remote ischemia in our study was applied at the contralateral upper arm including five minutes of ischemia with ten and finally fifteen minutes of reperfusion over three circles leading to an increase of cutaneous oxygen saturation at the anterolateral thigh skin territory, a significant increase of the capillary blood flow as well as a statistical significant decrease of the postcapillary filling pressure as a marker of venous stasis.
As our study elucidated the short term results of RIPC and documented the beneficial effect of the intermittent, repetitive component of RIPC on microcirculation, further studies should now focus on intermediate and long term effects of RIPC on cutaneous microcirculation. Another field of application of RIPC should also be part of further investigations calling muscular microcirculation as ischemia of muscle does not necessarily lead to muscle necrosis, but can lead to progressive microvascular dysfunction at an early stage with consecutive microcirculatory impairment as a vicious circle up to a compartment syndrome . Therefore, an increase of cutaneous oxygen saturation and capillary blood flow as well as a decrease of venous stasis as immediate effects of RIPC, which we demonstrated in our study, might also be beneficial in reoxygenation-associated inflammation due to reperfusion injury in muscular trauma or surgery.