Hypoxia Free radicals Reperfusion Injury RI HBO

Inadequate oxygen supply in compromised flaps according to Kerrigan and Daniel16 is the result of three hypoxic insults: a) direct ischemia from the interruption of cutaneous vessels, cell death within 13 hrs in cases of non restored flow and initiation of post-ischemic inflammatory process resulting in endothelial swelling b) expansion of the inflammatory reaction from the surgical injury itself c) vasoconstriction due to the release of catecholamines as nerve continuity is interrupted through the alpha adrenergic receptors.

Skin grafts survive only if enough oxygen diffuses from a non- hypoxic underlying bed at least for 24-48 hrs until the appearance of revascularization.

Hypoxia, through the interruption of aerobic metabolism, initiates catabolism of ATP to adenosine creating anaerobic metabolites like hypoxanthine an electron donor which in the presence of oxygen mediates the formation of free radicals: superoxide anion, and hydroxid peroxide or hydroxyl radical (if more electrons are added).

There are many types of radicals but those of most concern in biological systems are derived from oxygen and known collectively as reactive oxygen species.

Another important source of free radical production is the neutrophils through the cell membrane NADPH oxidase and degranulation.

The resumption of blood flow after a prolonged period of flow cessation causes an inflammatory reaction in the microcirculation the so-called ischemia reperfusion injury, (RI) or "no-reflow" phenomenon where the free radicals play an important role17.

The restoration of perfusion and oxygen delivery to hypoxic tissues after a certain period of ischemia normally should be related with reestablishment of aerobic metabolic balance and depletion of free radicals but instead of it far greater production of reactive oxygen intermediates may occur18.

Endothelial cellular injury, prostaglandins release, inflammatory cytokine secretion and presence of interstitial edema due to capillary leakage are some of the hypoxia and the RI induced effects19.

Zamboni et al.20 have demonstrated in a rat sceletal muscle "in vivo" after 4hrs of ischemia the important role of neutrophils in the apparition of RI. Leucocytes presented an increased adherence to the endothelium resulting in the occlusion of postcapillary venules and additionally in a significant vasococonstriction of arterioles. The adherence phenomenon was proved to be moderated by the action of "intercellular adhesion molecules" (ICAM -1), known as b2 integrins on the corresponding receptors (CD-11a, b, c, CD-18 chain) of the expressing neutrophils membrane surface21, 22.

As demonstrated in several studies23,24 ICAM-1 expression is not mediated by hypoxia alone but requires the co-existence of cytokines or a reperfusion period.

A cascade of interactions is induced by the action of free radicals, molecules highly unstable, upon the cellular membranes or on the membranes receptors, channels, proteins and nucleic acids.

The clinical effects depend on the involved area of the transplanted tissue as the hypoxia intensity varies between the central region and the distal parts the last ones being the most sensitive.

The role of free radicals and the phenomenon of RI have a very distinctive role in the pathophysiology of compromised flaps.

Experimental and clinical studies have demonstrated the improvement of skin /muscle flap survival subjected to hypoxia and RI after the administration of various free radical scavengers25, 26.

As the role of oxygen in the RI is the key factor it could be assumed that the use of HBO would enhance further the generation of free radicals and the rate of deleterious cascade in local microcirculation.

However, clinical and experimental experience has demonstrated that HBO not only does not promote RI but on the contrary it acts as antagonist20,

Thom et al.30 as well as Suzuki31 revealed that HBO may stop the neutrophil adhesion and the interaction of b2 -integrins on the CD-18 surface receptors expressed on neutrophils and endothelium.

Zamboni et al.20, 32 demonstrated also the efficacy of HBO in inhibiting leukocyte adherence. Thus in a study32 of a reperfused rat skin flap model after 8hrs of ischemia a significant improvement of tissue survival has been shown, after application of HBO. Using quantitative analysis Zamboni also showed that HBO impaired the leukocyte adherence on endothelium in post-ischemic skeletal muscle20.

Buras et al.33 recently suggested that the beneficial effect of HBO in RI through a decreased expression of ICAM-1 may be related to an induced eNOS synthesis, which may help explain also the protective effect of HBO treatment, if applied before RI in a rodent liver model34 .

Compromised free flaps are mostly submitted to RI and HBO use may be of major clinical value according to the experimental35 and clinical studies36.

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