**7. Discussion**

Vitamins with antioxidant properties such as vitamins A, C, and E have positive effects on I/R injury but they are not adequately effective when given alone. If they are used in combination with other vitamins and drugs with antioxidant properties, they work synergistically to decrease I/R injury. For instance, combined use of vitamin A and E in an animal model showed increase in flap survival with the help of their synergistic effect on reducing lipid peroxidation [47]. Also, vitamin E and iloprost (synthetic analog of prostacyclin PGI2) combination demonstrated that they attenuate reperfusion injury more efficiently than their separate use, in skeletal muscle I/R injury model [68]. In addition to these, Kayiran et al. [69] showed that combined usage of vitamins C, E, acetylcysteine, and prednisolone alleviated the results of ischemia and enhanced the flap survival on free radial forearm flap. There is a wide range use of substances in the literature to prevent I/R injury, but there is no single ideal drug that can overcome this damage; so, we think that the use of combined therapy is more successful in achieving impressive results.

Because high amounts of ROS are produced in I/R injury, the amount of certain antioxidants decreases. Depletion of antioxidants does not always mean oxidative tissue damage has happened: it might simply indicate that the antioxidant system has removed the ROS and thereby consumed the present antioxidants to protect the tissues [70]. Tissue damage occurs if the ROS amount outruns the capacity of the body defense system. In other words, administration of antioxidants prior to flap surgery may help to avoid unfavorable effects of I/R injury.

Trolox equivalent antioxidant capacity (TEAC) is a measure that shows the capacity of the present hydrophilic antioxidants. In other words, it demonstrates the antioxidant level on a certain amount of tissue. According to Van den Heuvel et al. [31], TEAC concentrations was not differ 30 min later after reperfusion but there was an important decrease after 1 h of reperfusion. The TEAC concentrations were recovered in the next 1 h, showing us the body was replacing the antioxidants. These findings suggest that first hour after reperfusion is the most vulnerable period of flap to I/R injury and timing of antioxidant replacement may have an important role in preventing this injury too.

Lipids are usually primary target of free oxygen radicals in oxidative damage and lipid oxidation occurs when they exposed free radicals. Lipid oxidation is a process that generates many end products. Between these products, MDA, which is an aldehyde, is the most studied one among them [71]. Because it is the end product of the lipid oxidation pathway, measurement of MDA levels is a commonly used indicator of oxidative damage [72]. Also, MDA might help us to monitor the reaction of the body against the antioxidant support. In other words, if MDA levels are high, we can increase the antioxidant support to body in I/R injury.

Measuring MDA levels helps us to determine antioxidant therapy protocol. However, we cannot increase the dosage of antioxidants easily because they are not only antioxidant but also have prooxidant properties. Helpful effects of antioxidants are usually higher in the studies that were done in vitro comparing with the studies that were done in vivo. This fact is called "The antioxidant paradox" [73]. Many antioxidants can produce ROS at higher doses. But if they are administered at

**397**

**Author details**

**8. Conclusion**

provided the original work is properly cited.

\*Address all correspondence to: drmbozkurt@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Mehmet Bozkurt\*, Melihcan Sezgic, Percin Karakol, Can Uslu and Tevfik Balikci Health and Science University, Istanbul Bagcılar Hospital, Istanbul, Turkey

*The Effect of Antioxidants on Ischemia-Reperfusion Injury in Flap Surgery*

studies are necessary in order to determine completely how they act.

I/R injury in addition to the antioxidants described previously.

think that they will increase their medical use in the future.

even higher doses, they can generate massive amounts of ROS that the body cannot handle. So, they can worsen oxidative stress and cause necrosis. For instance, ascorbic acid, which is widely known as a powerful antioxidant vitamin in human body, can reduce most of the ROS and other radicals. On the other hand, it has been shown that it has a prooxidant act in humans even at a dose of 500 mg/day [74]. Moreover, according to Mendes-da-Silva et al. [75], ascorbic acid was served as an antioxidant on rats at 30/mg/kg/day but they were discovered opposite effects at 60/ mg/kg/day. In light of these findings, since the use of antioxidants is like a doubleedged sword, careful dose adjustment is required for use in I/R injury. Further

The effect of antioxidants on I/R injury is still under investigation. There are also substances with antioxidant properties such as flavonoids [76], thioredoxin [77], propofol [78], ebselen [79], edaravone [80], etc. which also have positive effects on

I/R injury is still the most challenging problem in flap surgery. Prolonged ischemia of the flap causes irreversible infarct and flap loss, and this increases the patient morbidity. Because free radical formation is a significant step in pathophysiology of I/R injury, the help of antioxidants on I/R injury is cannot be disregarded. There have been a lot of studies proving this fact so there is a need for further studies for a better understanding of their certain effects. In this chapter, we tried to show how the antioxidants affect the I/R injury and how effective their use is. In conclusion, although the efficacy of antioxidants is not yet fully understood, we

*DOI: http://dx.doi.org/10.5772/intechopen.85500*

#### *The Effect of Antioxidants on Ischemia-Reperfusion Injury in Flap Surgery DOI: http://dx.doi.org/10.5772/intechopen.85500*

even higher doses, they can generate massive amounts of ROS that the body cannot handle. So, they can worsen oxidative stress and cause necrosis. For instance, ascorbic acid, which is widely known as a powerful antioxidant vitamin in human body, can reduce most of the ROS and other radicals. On the other hand, it has been shown that it has a prooxidant act in humans even at a dose of 500 mg/day [74]. Moreover, according to Mendes-da-Silva et al. [75], ascorbic acid was served as an antioxidant on rats at 30/mg/kg/day but they were discovered opposite effects at 60/ mg/kg/day. In light of these findings, since the use of antioxidants is like a doubleedged sword, careful dose adjustment is required for use in I/R injury. Further studies are necessary in order to determine completely how they act.

The effect of antioxidants on I/R injury is still under investigation. There are also substances with antioxidant properties such as flavonoids [76], thioredoxin [77], propofol [78], ebselen [79], edaravone [80], etc. which also have positive effects on I/R injury in addition to the antioxidants described previously.
