Hypoxemic reperfusion of ischemic states: an alternative approach for the attenuation of oxidative stress mediated reperfusion injury

Marios-Konstantinos Tasoulis
Emmanuel E Douzinas
Hypoxemic reperfusion of ischemic states: an alternative approach for the attenuation of oxidative stress mediated reperfusion injury
10.1186/s12929-016-0220-0R E V I E WReperfusion injuryHypoxemic reperfusionOxidative stressReactive oxygen species
Ischemia and reperfusion (I/R)induced injury has been described as one of the main factors that contribute to the observed morbidity and mortality in a variety of clinical entities, including myocardial infarction, ischemic stroke, cardiac arrest and trauma. An imbalance between oxygen demand and supply, within the organ beds during ischemia, results in profound tissue hypoxia. The subsequent abrupt oxygen re-entry upon reperfusion, may lead to a burst of oxidative aggression through production of reactive oxygen species by the primed cells. The predominant role of oxidative stress in the pathophysiology of I/R mediated injury, has been well established. A number of strategies that target the attenuation of the oxidative burst have been tested both in the experimental and the clinical setting. Despite these advances, I/R injury continues to be a major problem in everyday medical practice. The aim of this paper is to review the existing literature regarding an alternative approach, termed hypoxemic reperfusion, that has exhibited promising results in the attenuation of I/R injury, both in the experimental and the clinical setting. Further research to clarify its underlying mechanisms and to assess its efficacy in the clinical setting is warranted.

Background

Tissue hypoxia due to ischemia is the common denominator in a variety of clinical emergencies of either regional distribution such as myocardial infarction and mesenteric embolism, or of systemic involvement such as cardiac arrest and hemorrhagic shock, both of which represent the equivalent of whole body ischemia.

The aforementioned conditions are sometimes fatal because of the injury that lurks to appear, the so called ischemiareperfusion (I/R) injury. This represents somehow, the cost of optimal reperfusion or effective resuscitation from longstanding insults of ischemia. Reperfusion injury does not occur during the preceding ischemic period; rather, this injury refers to a causal event associated with reperfusion. This event may result in a number of detrimental effects including multiple organ failure (MOF) and death. Over the last several decades, a variety of treatment modalities have been evaluated to attenuate I/R injury. Hypoxemic reperfusion, in particular, may be particularly promising. The aim of this review is to summarize the existing literature regarding the underlying mechanisms and potential applications of hypoxemic reperfusion in a variety of clinical scenarios of regional and systemic I/R injury.

Review

Strategies of reperfusion injury prevention

Reactive oxygen species have been found to play a key role in the pathophysiology of I/R injury [1]. Oxidative stress generated during reperfusion, may mediate injury to the insulted tissues. This phenomenon is part of the term «oxygen paradox», in which reoxygenation of an ischemic tissue produces a degree of injury that greatly exceeds the injury induced by ischemia alone [2]. However, oxidative stress, contributes to I/R injuryinduced damage in a consecutive twophase pattern. In addition to its direct cytotoxic effects, the burst of free radicals, generated by oxidative stress, also induces the formation of inflammatory mediators [3] through redoxmediated signalling pathways, leading to post ischemiareperfusion inflammatory injury [2,3]. These oxidative and inflammatory responses have been implicated in the development of MOF, a detrimental manifestation often following I/R.

The above knowledge has led medical research to focus on the development of potential strategies aimed at eliminating the effects of reactive oxygen species (ROS) and of the systemic inflammatory response during reperfusion. Suggested methods include:

use of antioxidants in order to minimize the oxidative stress [4][5][6][7] scavengers for the removal of metabolic waste preconditioning techniques (ischemic, hypoxic, pharmacologic and remote ischemic preconditioning) to prepare cells to better respond to the forthcoming stress [8][9][10][11][12][13][14][15][16][17] Despite the proven beneficial effects, all the above strategies share one common disadvantage: they lack effectiveness when they are applied after or during reperfusion/resuscitation. This limits their usefulness in the clinical setting. Antioxidants should be administered ideally before ischemia and reperfusion in order to achieve their maximum effect. In fact, most available evidence regarding their favorable effects derives from studies in which antioxidants were used as pre-treatment [5,7]. Moreover, their use, even in combination with scavengers, does not completely abolish the ensuing injury. The same applies for the use of preconditioning techniques. The rationale of these techniques is to pre-medicate the patient, which may not be feasible in all clinical scenarios. Therefore, the application of these strategies in the clinical setting may be limited [14-16, 18, 19]. A recent metaanalysis questioned the efficacy of ischemic preconditioning in the setting of liver surgery [20]. Similarly, remote ischemic preconditioning, a technique that held great promise for its demonstrated favorable effects, did not exert the expected outcomes when tested in clinical trials [21][22][23].

Despite the controversial results in the clinical setting, the existing literature regarding these strategies provides additional evidence, confirming the oxidative nature of the injury following reperfusion. The pivotal role of oxidative stress mediated reperfusion injury has been well established. Using a rabbit experimental model, it was shown that resuscitation from hemorrhagic shock resulted in acute lung injury with enhanced oxidative and inflammatory pulmonary responses. However, the degree of injury correlated only with the extent of oxidative aggression [24].

Hypoxemic reperfusion

Given that the abundance of oxygen supply, initially during reperfusion, produces a burst of ROS generation, the important question was whether this phenomenon could be attenuated by manipulating the oxygen content in the initial blood perfusate in order to meet with the adapted -at low cellular energy level-needs during ischemia.

Over the last years, a growing body of literature examines the effect of ischemic post-conditioning, which seems to be a promising approach [25][26][27][28][29][30]. This method is based on the concept that gradual reperfusion of a previously ischemic tissue, interrupted with short-lived episodes of ischemia, might yield favorable results. A closely related technique, termed "remote ischemic postconditioning", involves initiation of transient episodes of ischemia in a remote tissue or organ at the time of reperfusion [31][32][33][34]. A third, relatively new approach, similar to these is hypoxic post-conditioning, characterized by reperfusion under normoxia alternated with periods of hypoxia [35][36][37][38]. This is where hypoxemic reperfusion appears. It is about gradually increasing the FiO 2 of the reperfusate from a lower level in order to maintain P a O 2 levels of 30 -35 mmHg, initially during reperfusion, to gradually achieve P a O 2 levels of 95 -105 mmHg at the end of the resuscitation period. Historically, the accepted dogma was to give as much oxygen as possible to treat ischemic states. However, to deliver oxygen in plenty, particularly early in reperfusion, may only lead to higher quantities of ROS. Therefore, the imperative is to supply sufficient oxygen to meet tissue oxygen demand to maintain vital functions while minimizing reperfusion injury related to an abundance of ROS. Experimental findings indicate a significant correlation between P a O 2 and the phosphocreatine/inorganic phosphate ratio or intracellular pH. However, for P a O 2 ranging from 130 to 33 mmHg, metabolite changes were not significant. Both the ratio as well as the intracellular pH decreased significantly when P a O 2 was lowered below 33 and 28 mmHg respectively [39]. Moreover, the seemingly paradoxical idea of hypoxemic reperfusion is very similar to the aforementioned strategies of post-conditioning in terms of physiology. What is common in these two methods is the lower delivery of oxygen early during reperfusion so as not to provide it in abundance to form ROS. How is this possible? Delivery of oxygen is calculated by the following formula: DO 2 = CO × C a O 2 (C a O 2 = 13.4 × [Hb] × S a O 2 + 0.03 P a O 2 ). During post-conditioning the altered parameter is the cardiac output (CO) through the gradual reperfusion whereas during hypoxemic reperfusion the altered parameter is S a O 2 and P a O 2 through the gradual increase of FiO 2 .

The basic underlying concept of hypoxemic reperfusion is that when reperfusion of a previously ischemic tissue takes place under hypoxemia, the cells will not be supplied with an abundance of oxygen, which will be available for ROS production (Fig. 1a). Alternatively, it is hypothesized that the gradual reintroduction of oxygen in increasing concentration during reperfusion, corresponding to the increasing tissue requirements, may be used by the mitochondria for the generation of ATP and the restoration of the cell's energy resources (Fig. 1b). Therefore, hypoxemic reperfusion represents a strategy that can be applied after the occurrence of the ischemic insult, at the beginning of reperfusion. This could be a significant advantage when compared to other reperfusion strategies, including the use of antioxidants and preconditioning, since these techniques need to be implemented before reperfusion to show their beneficial effects [5,7,[14][15][16]. Another potential advantage of hypoxemic reperfusion compared to the use of antioxidants, is that it aims to prevent ROS production rather than eliminate their deleterious effects. Moreover, hypoxemic reperfusion may be advantageous compared to post-conditioning strategies since blood flow is restored offering better replenishment from metabolic wastes. However, apart from the theory, the method should be examined in vivo. Indeed the existing evidence, summarized in Table 1, exhibit remarkably favorable results in various applications both in the experimental and the clinical setting.

Gastrointestinal tract reperfusion injury

Ischemiareperfusion induced injury of the gastrointestinal tract can ensue from a variety of clinical conditions such as mesentery artery embolism. In 1988, Perry et al. showed, for the first time, that gradual reintroduction of oxygen reduced reperfusion injury as evidenced by decreased gastric mucosal bleeding after ischemia in a cat experimental model [40].

A subsequent set of experiments, further demonstrated the favorable effect of hypoxemic reperfusion in the setting of I/R injury of the gastrointestinal tract. Specifically, using a porcine model of intestinal ischemia, through clamping of the superior mesenteric artery [41,42], it was shown that hypoxemic reperfusion resulted in decreased gut barrier dysfunction as evidenced by the lower incidence of positive Limulus test [41]. Both the oxidative and the inflammatory responses were also attenuated as demonstrated by the decrease in intestinal mucosa malondialdehyde (MDA) [42] and portal blood interleukin (IL) -1b levels [41]. The application of this method resulted in a decrease of the observed histopathologic injury not only of the intestine [41] but also of remote organs such as the heart [42] and lung [41]. This finding implies a systemic favorable effect and highlights the potential role of hypoxemic reperfusion in the prevention of MOF through attenuation of oxidative and inflammatory responses. Furthermore, animals that underwent hypoxemic reperfusion had a superior hemodynamic profile as evidenced by mean arterial pressure preservation, lower need for inotropic support, and a trend towards S O 2 restoration [42].

Brain reperfusion injury

The brain is thought to be the most vulnerable organ in hypoxic challenges. Compromise of cerebral perfusion and thus oxygen delivery may follow cardiac arrest, traumatic brain injury, ischemic stroke etc. In these cases, the restoration of blood flow may lead to reperfusion injury. The efficacy of gradual reintroduction of oxygen in the previously ischemic brain has been tested in a dog experimental model by Burda et al [43]. They used a global brain ischemia model produced by cross-clamping of the left subclavian artery and the brachiocephalic trunk at the point of their emergence from the aorta and showed that the animals that underwent reperfusion under hypoxemia   [44,45], where hypoxemic reperfusion was found to result in improved neurological outcome as evidenced by the superior Overall Performance Category (OPC) score [44], decreased brain histopathologic damage [45] and reduced lipid peroxidation [44]. There has, however, been one study in which hypoxemic reperfusion was found to exacerbate neurological injury [46]. In a porcine model designed to resemble the clinical scenario of infants undergoing deep hypothermic circulatory arrest with diminished cerebral blood flow as employed during surgical intervention for complex congenital heart lesions, investigators applied maintained hypoxemic arterial oxygen tensions (P a O 2 , 40 -50 mmHg) throughout the reperfusion period without return to normoxemia [46]. While this was found to lead to worse outcomes, this method cannot be compared with other studies in which the reperfusion took place under hypoxemic conditions with gradual return to normoxemia.

Myocardial reperfusion injury

Myocardial reperfusion injury represents a devastating entity encountered in the clinical setting as a result of various conditions including percutaneous coronary intervention after acute myocardial infarction and cardiac surgery. The promising results of hypoxemic reperfusion have led to testing of this strategy in the setting of myocardial reperfusion injury, both in experimental and clinical studies.

Abdel -Rahman et al. used a porcine experimental model of cardiopulmonary bypass with aortic clamping and cardioplegic arrest to test the efficacy of the so-called gradual reoxygenation in the attenuation of myocardial reperfusion injury [47]. The results of their study indicate that applying hypoxemia at the onset of the reperfusion period with gradual return to normoxemia resulted in significantly less impairment of myocardial function, decreased myocardial injury and reduced oxidative damage.

The same group designed and conducted a prospective study, using nineteen consecutive patients who underwent cardiac surgery with cardiopulmonary bypass for scheduled coronary artery bypass grafting as the study's population [48]. Graded reoxygenation at the beginning of the reperfusion period led to a decrease in myocardial oxidative injury as signified by the lower MDA blood levels.

Generalized ischemia -reperfusion injury

Graded post-ischemic reoxygenation has also been the topic of investigation by Maršala and his group in the setting of aortic clamping induced ischemia. Using a rabbit experimental model, they found that gradual reoxygenation during reperfusion after infrarenal aortic occlusion, resulted in the preservation of the cytoplasmic and nuclear structures of the lumbosacral dorsal root ganglia neurons [49,50]. In a similar model of aortic clamping-induced spinal cord ischemia, they showed that the application of gradual reoxygenation reduced neuropathological damage [51], decreased bloodbrain barrier permeability [52] and attenuated neuronal argyrophilia and reperfusion injuryinduced alterations in neuronal organelles [53].

However, one study by Lehmann et al. using a porcine model of complete lower torso ischemia, found that hypoxemic reperfusion resulted in a deteriorated hemodynamic profile, increased lactic acidosis and higher inotropic agents requirements compared to normoxemic reperfusion [54]. A possible explanation for these findings which are discrepant from that of other studies is that in this study, there was a long aortic cross-clamp period, perhaps resulting in greater injury severity and ischemic insult.

Hemorrhagic shockresuscitation

Hemorrhagic shock and resuscitation represents a model of whole body I/R injury. In a pilot study, using a rat  Table summarizes the data of the available studies of hypoxemic reperfusion presenting the setting, the model of ischemiareperfusion injury studied, the reperfusion protocol and the main outcomes P a O 2 partial arterial oxygen pressure, SMA superior mesenteric artery, FiO 2 fraction of inspired oxygen, MAP mean arterial pressure, CPB cardio-pulmonary bypass, CABG coronary artery bypass grafting model of controlled hemorrhagic shock, hypoxemic resuscitation resulted in superior hemodynamic stabilization and less oxidative and inflammatory responses as evidenced by the decreased MDA and tumor necrosis factor alpha (TNF-a) serum levels [55]. Similar results were shown in a rabbit experimental model. Application of hypoxemic resuscitation was associated with more efficient blood pressure restoration as well as attenuation of the oxidative insult exerted by normoxemic resuscitation [3]. This was shown by the decreased production of ROS as assessed by flow cytometry, reduced MDA and higher ratio of reduced to total glutathione levels. Moreover, hypoxemic resuscitation resulted in attenuation of the inflammatory response as evidenced by the significantly lower serum levels of TNF-a, IL-1b and IL-6. These effects could be attributed to the lower stimulation of p38 mitogen activated protein kinase (MAPK)mediated production of inflammatory cytokines by monocytes [56]. Additionally, using this combined in vivo and in vitro model, it was shown that the serum of normoxemically resuscitated animals could prime the otherwise inert U937 monocyte like cells for the production of inflammatory cytokines. This effect was abolished when the cells were incubated with the serum drawn from animals that were resuscitated under hypoxemic conditions, highlighting a favorable systemic effect [56]. The beneficial role of this strategy in the attenuation of the systemic inflammatory response is also supported by the resulting lower serum levels of angiopoietin-2, a key player in vascular homeostasis and inflammation [57]. Systemic inflammatory response and tissue hypoperfusion following ischemia and dysregulated vascular endothelial function are the major contributors of MOF. Taken together, these results could support the hypothesis that hypoxemic reperfusion confers protection against MOF through attenuation of the inflammatory response and preservation of vascular homeostasis. Hypoxemic reperfusion has also been found to protect from lung injury and pulmonary dysfunction, which constitute a significant problem encountered after resuscitation from hemorrhagic shock [58,59]. The favorable effects of gradual reintroduction of oxygen, include preservation of pulmonary capillary endothelial angiotensin converting enzyme activity, lower lung tissue myeloperoxidase (MPO) activity, lower lung injury histopathological score and lower MDA and intracellular adhesion molecule (ICAM) -1 and vascular cell adhesion molecule (VCAM) -1 expression levels. In another set of experiments, hypoxemic resuscitation was associated with decreased bronchoalveolar lavage (BAL) ROS levels as measured by flow cytometry as well as reduced inflammatory cytokine levels including TNF-a, IL-1b and IL-6. In addition, the nitrotyrosine score, as a marker of nitrosative stress mediated injury, was higher in the normoxemic resuscitation group of animals. Moreover, another favorable effect of hypoxemic resuscitation from hemorrhagic shock is the prevention of post-ischemic liver injury through the attenuation of nitrosative and oxidative stresses [60]. These effects were evidenced by the lower serum ROS and cytokines (TNF-a, IL-1b and IL-6) levels, the lower hepatic MDA levels and the decreased hepatic MPO and endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) expression. These results, regarding the lower degree of injury of isolated organs (i.e. lung and liver) also highlight the potential beneficial role of hypoxemic reperfusion in the prevention of MOF. More recently, Luo et al. [61] compared the effects of normoxic, hyperoxic, hypoxemic and gradual resuscitation from hypoxia to hyperoxia (gradually increased oxygen administration -GIOA technique) in a rat experimental model. The authors showed that hypoxemic resuscitation resulted in worse hemodynamic profile as evidenced by the significantly lower pulse pressure as well as lower liver tissue oxygen partial pressure compared to GIOA resuscitation. The hypoxemic mode of reperfusion showed significantly lower liver injury, oxidative and inflammatory responses, only compared to hyperoxic resuscitation, while no statistically significant differences were demonstrated between GIOA and hypoxemic groups. However, the discordance between these results and previously published data [3] could be attributed to the relatively shorter follow up period in Luo's study [61]. Longer follow up period in that study, could eventually unmask detrimental effects of the applied hyperoxemia in the context of GIOA, in contrast to normoxemia.

Conclusions

The pivotal role of oxidative stress mediated injury after ischemia and reperfusion has been well established. Over the last decades, medical research has focused on the elucidation of the underlying pathophysiologic mechanisms in an attempt to develop strategies to attenuate this I/R injury. Hypoxemic reperfusion has been proposed as a technique aimed at the elimination of the oxidative burst that leads to the downstream cascade of free radicals and inflammation leading to multiple organ injury. This method has shown promise in various cases of I/R injury both in the experimental and clinical setting. However, further research both to clarify its underlying basic mechanisms and to assess its efficacy in the clinical setting is warranted.

Fig. 1
1Representation of biochemical events that lead to the production of reactive oxygen species (ROS) and subsequent tissue damage during ischemia and reperfusion (Panel a). Panel b represents the hypothesis of restoration of cellular energy resources achieved by reperfusion of the previously ischemic tissues under lower P a O 2 (hypoxemic reperfusion) with gradual return to normoxemia

Table 1
1Summary of hypoxemic reperfusion studiesStudy
Type of study Model of ischemia
Reperfusion protocol
Outcome

Perry et al. [40]
Experimental Celiac artery ischemia through
adjustable screw clamp

P a O 2 = 34 mmHg for 1 h before
return to normal perfusion

↓gastric mucosal bleeding

Douzinas et al. [41]
Experimental SMA clamping
P a O 2 = 30-35 mmHg with gradual
return to normoxemia over a 2 h
period

↓intestinal mucosa and
lung injury

↓inflammatory response

Douzinas et al. [42]
Experimental SMA clamping
P a O 2 = 30-35 mmHg with gradual
return to normoxemia over a 2 h
period

↑hemodynamic profile

↓oxidative response

↓myocardial injury

Burda et al. [43]
Experimental Clamping of left subclavian artery
and brachiocephalic trunk

P a O 2 = 37.5 mmHg with gradual
return to normoxemia over a
15-30 minute period

↑cerebral protein synthesis

Douzinas et al. [44]
Experimental Global cerebral ischemic insult through
decrease of MAP, bilateral clamping
of carotid arteries and cessation
of respiration

FiO 2 = 0.12 with gradual increase to
achieve P a O 2 = 100 mmHg over a 1 h
period

↑neurological outcome

↓oxidative response

Douzinas et al. [45]
Experimental Global cerebral ischemic insult through
decrease of MAP, bilateral clamping of
carotid arteries and cessation of respiration

P a O 2 = 30-35 mmHg with gradual
increase to achieve P a O 2 = 100 mmHg
over a 1 h period

↓cerebral injury

Hickey et al. [46]
Experimental Deep hypothermic circulatory arrest
P a O 2 = 40-50 mmHg throughout the
reperfusion period

↑cerebral injury

Abdel-Rahman et al. [47] Experimental Aortic clamping and cardioplegic arrest P a O 2 = 40-50 mmHg gradually
increased towards normoxemia over
a 10 minute period

↑hemodynamic profile

↓myocardial injury

↓oxidative response

Abdel-Rahman et al. [48] Clinical
CPB for CABG
P a O 2 = 50 mmHg with return to
normoxemia over a 5 minute period

↓oxidative response

Fercakova et al. [49]
Experimental Infrarenal aortic occlusion
Graded postischemic reoxygenation ↑neuroprotection

Daxnerova et al. [50]
Experimental Infrarenal aortic occlusion
Graded postischemic reoxygenation ↑neuroprotection

Marsala et al. [51]
Experimental Infrarenal aortic occlusion
Graded postischemic reoxygenation ↓neuropathological
damage

Orendacova et al. [52]
Experimental Infrarenal aortic occlusion
P a O 2 = 48 mmHg with gradual return
to normoxemia over a 15 minute
period

↑neuroprotection

Lukacova et al. [53]
Experimental Infrarenal aortic occlusion
P a O 2 = 48 ± 12 mmHg with gradual
return to normoxemia over a
30 minute period

↑neuroprotection

Lehmann et al. [54]
Experimental Supraceliac aortic clamp
P a O 2 = 25-35 mmHg for 30 minutes
with gradual return to normoxemia
over a 90 minute period

↓hemodynamic profile

Douzinas et al. [55]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.12 with gradual increase to
FiO 2 = 0.21 over a 40 minute period

↑hemodynamic profile

↓oxidative response

↓inflammatory response

Douzinas et al. [3]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.08-0.10 with gradual
increase to FiO 2 = 0.21 over a
60 minute period

↑hemodynamic profile

↓oxidative response

↓inflammatory response

Douzinas et al. [56]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.08-0.10 with gradual
increase to FiO 2 = 0.21 over a
60 minute period

↓oxidative response

↓inflammatory response

Douzinas et al. [57]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.08-0.10 with gradual
increase to FiO 2 = 0.21 over a
60 minute period

↑vascular homeostasis

Douzinas et al. [58]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.08-0.10 with gradual
increase to FiO 2 = 0.21 over a
60 minute period

↓oxidative response

↓lung injury

Table 1
1Summary of hypoxemic reperfusion studies (Continued)Douzinas et al. [59]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.08-0.10 with gradual
increase to FiO 2 = 0.21 over a
60 minute period

↓oxidative response

↓inflammatory response

↓lung injury

Douzinas et al. [60]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.08-0.10 with gradual
increase to FiO 2 = 0.21 over a
60 minute period

↓oxidative response

↓inflammatory response

↓liver injury

Luo et al. [61]
Experimental Hemorrhagic shock -exsanguination
FiO 2 = 0.11 with gradual increase to
FiO 2 = 0.21 over a 60 minute period

↓hemodynamic profile

─oxidative response

─inflammatory response

Abbreviation ATP: adenosine triphosphate; BAL: bronchoalveolar lavage; C a O 2 : arterial oxygen content; CO: cardiac output; DO 2 : oxygen delivery; eNOS: endothelial nitric oxide synthase; FiO 2 : fraction of inspired oxygen; GIOA: gradually increased oxygen administration; Hb: hemoglobin; I/R: ischemiareperfusion; ICAM: intracellular adhesion molecule; IL: interleukin; iNOS: inducible nitric oxide synthase; MAPK: mitogen activated protein kinase; MDA: malondialdehyde; MOF: multiple organ failure; MPO: myeloperoxidase; OPC: overall performance score; P a O 2 : partial arterial oxygen pressure; ROS: reactive oxygen species; S a O 2 : arterial oxygen saturation; S O 2 : mixed oxygen venous saturation; TNF: tumor necrosis factor; VCAM: vascular cell adhesion molecule.
AcknowledgementsThe authors are grateful to Dr. Anees B. Chagpar, MD, MSc, MPH, MA, MBA, FRCS(C), FACS, Associate Professor of Surgery, Yale University School of Medicine for editorial assistance and language review of the manuscript.Competing interestsThe authors declare that they have no competing interests.Authors' contributions MKT: Carried out the search of the literature, analysis of the results and drafted the manuscript. EED: Conceived the idea and participated in the analysis of the results and drafted the manuscript. Both authors read and approved the final manuscript.• We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal Submit your next manuscript to BioMed Central and we will help you at every step:
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The hepatic soluble guanylyl cyclase-cyclic guanosine monophosphate pathway mediates the protection of remote ischemic preconditioning on the microcirculation in liver ischemia-reperfusion injury. M Abu-Amara, Yang Sy, A Quaglia, P Rowley, N Tapuria, B Fuller, Transplantation. 939Abu-Amara M, Yang SY, Quaglia A, Rowley P, Tapuria N, Fuller B, et al. The hepatic soluble guanylyl cyclase-cyclic guanosine monophosphate pathway mediates the protection of remote ischemic preconditioning on the microcirculation in liver ischemia-reperfusion injury. Transplantation. 2012;93(9):880-6.

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Meta-analysis of ischaemic preconditioning for liver resections. S O'neill, S Leuschner, S J Mcnally, O J Garden, S J Wigmore, E M Harrison, Br J Surg. 10013O'Neill S, Leuschner S, McNally SJ, Garden OJ, Wigmore SJ, Harrison EM. Meta-analysis of ischaemic preconditioning for liver resections. Br J Surg. 2013;100(13):1689-700.

A Double Blind Randomized Clinical Trial of Remote Ischemic Conditioning in Live Donor Renal Transplantation. M L Nicholson, C J Pattenden, A D Barlow, J P Hunter, G Lee, S A Hosgood, Medicine. 94311316Nicholson ML, Pattenden CJ, Barlow AD, Hunter JP, Lee G, Hosgood SA. A Double Blind Randomized Clinical Trial of Remote Ischemic Conditioning in Live Donor Renal Transplantation. Medicine. 2015;94(31):e1316.

A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. P Meybohm, B Bein, O Brosteanu, J Cremer, M Gruenewald, C Stoppe, N Engl J Med. 37315Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, et al. A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N Engl J Med. 2015;373(15):1397-407.

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. D J Hausenloy, L Candilio, R Evans, C Ariti, D P Jenkins, S Kolvekar, N Engl J Med. 37315Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, et al. Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. N Engl J Med. 2015;373(15):1408-17.

High concentrations of reactive oxygen species in the BAL fluid are correlated with lung injury in rabbits after hemorrhagic shock and resuscitation. M K Tasoulis, O Livaditi, M Stamatakos, C Stefanaki, P Paneris, P Prigouris, Tohoku J Exp Med. 2193Tasoulis MK, Livaditi O, Stamatakos M, Stefanaki C, Paneris P, Prigouris P, et al. High concentrations of reactive oxygen species in the BAL fluid are correlated with lung injury in rabbits after hemorrhagic shock and resuscitation. Tohoku J Exp Med. 2009;219(3):193-9.

Immediate postconditioning during reperfusion attenuates intestinal injury. K X Liu, Y S Li, W Q Huang, S Q Chen, Z X Wang, J X Liu, Intensive Care Med. 355Liu KX, Li YS, Huang WQ, Chen SQ, Wang ZX, Liu JX, et al. Immediate postconditioning during reperfusion attenuates intestinal injury. Intensive Care Med. 2009;35(5):933-42.

Ischaemic postconditioning reduces infarct size: systematic review and meta-analysis of randomized controlled trials. C Touboul, D Angoulvant, N Mewton, F Ivanes, D Muntean, F Prunier, Arch Cardiovasc Dis. 1081Touboul C, Angoulvant D, Mewton N, Ivanes F, Muntean D, Prunier F, et al. Ischaemic postconditioning reduces infarct size: systematic review and meta-analysis of randomized controlled trials. Arch Cardiovasc Dis. 2015;108(1):39-49.

Cardioprotective role of ischemic postconditioning in acute myocardial infarction: a systematic review and meta-analysis. A R Khan, A A Binabdulhak, Y Alastal, S Khan, B M Faricy-Beredo, F K Luni, Am Heart J. 1684e4Khan AR, Binabdulhak AA, Alastal Y, Khan S, Faricy-Beredo BM, Luni FK, et al. Cardioprotective role of ischemic postconditioning in acute myocardial infarction: a systematic review and meta-analysis. Am Heart J. 2014;168(4):512-21. e4.

Protection against renal ischemia-reperfusion injury by ischemic postconditioning. E K Van Den Akker, O C Manintveld, D A Hesselink, R W De Bruin, J N Ijzermans, F J Dor, Transplantation. 9511van den Akker EK, Manintveld OC, Hesselink DA, de Bruin RW, Ijzermans JN, Dor FJ. Protection against renal ischemia-reperfusion injury by ischemic postconditioning. Transplantation. 2013;95(11):1299-305.

Attenuation of endoplasmic reticulum stress and mitochondrial injury in kidney with ischemic postconditioning application and trimetazidine treatment. A Mahfoudh-Boussaid, M A Zaouali, T Hauet, K Hadj-Ayed, A H Miled, S Ghoul-Mazgar, J Biomed Sci. 1971Mahfoudh-Boussaid A, Zaouali MA, Hauet T, Hadj-Ayed K, Miled AH, Ghoul-Mazgar S, et al. Attenuation of endoplasmic reticulum stress and mitochondrial injury in kidney with ischemic postconditioning application and trimetazidine treatment. J Biomed Sci. 2012;19:71.

Ischemic postconditioning attenuates liver warm ischemia-reperfusion injury through Akt-eNOS-NO-HIF pathway. J Y Guo, T Yang, X G Sun, N Y Zhou, F S Li, D Long, J Biomed Sci. 1879Guo JY, Yang T, Sun XG, Zhou NY, Li FS, Long D, et al. Ischemic postconditioning attenuates liver warm ischemia-reperfusion injury through Akt-eNOS-NO-HIF pathway. J Biomed Sci. 2011;18:79.

Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. F Kerendi, H Kin, M E Halkos, R Jiang, A J Zatta, Z Q Zhao, Basic Res Cardiol. 1005Kerendi F, Kin H, Halkos ME, Jiang R, Zatta AJ, Zhao ZQ, et al. Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res Cardiol. 2005;100(5):404-12.

Remote ischemic pre-and postconditioning improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation. J Xu, S Sun, X Lu, X Hu, M Yang, W Tang, Crit Care Med. 431Xu J, Sun S, Lu X, Hu X, Yang M, Tang W. Remote ischemic pre-and postconditioning improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation. Crit Care Med. 2015;43(1):e12-8.

Remote ischemic postconditioning protects against gastric mucosal lesions in rats. T Wang, Y T Zhou, X N Chen, A X Zhu, B H Wu, World J Gastroenterol. 2028Wang T, Zhou YT, Chen XN, Zhu AX, Wu BH. Remote ischemic postconditioning protects against gastric mucosal lesions in rats. World J Gastroenterol. 2014;20(28):9519-27.

Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. G Crimi, S Pica, C Raineri, E Bramucci, De Ferrari, G M Klersy, C , J Am Coll Cardiol Intv. 610Crimi G, Pica S, Raineri C, Bramucci E, De Ferrari GM, Klersy C, et al. Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. J Am Coll Cardiol Intv. 2013;6(10):1055-63.

Hypoxic postconditioning enhances the survival and inhibits apoptosis of cardiomyocytes following reoxygenation: role of peroxynitrite formation. H C Wang, H F Zhang, W Y Guo, H Su, K R Zhang, Q X Li, Apoptosis. 118Wang HC, Zhang HF, Guo WY, Su H, Zhang KR, Li QX, et al. Hypoxic postconditioning enhances the survival and inhibits apoptosis of cardiomyocytes following reoxygenation: role of peroxynitrite formation. Apoptosis. 2006;11(8):1453-60.

Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+ overload. H Y Sun, N P Wang, F Kerendi, M Halkos, H Kin, R A Guyton, Am J Physiol Heart Circ Physiol. 2884Sun HY, Wang NP, Kerendi F, Halkos M, Kin H, Guyton RA, et al. Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+ overload. Am J Physiol Heart Circ Physiol. 2005;288(4):H1900-8.

Efficacy and mechanism of hypoxic postconditioning in salvage of ex vivo human rectus abdominis muscle from hypoxia/reoxygenation injury. A Naparus, H Ashrafpour, S O Hofer, T Zhong, N Huang, N J Cahoon, Eur J Pharmacol. 6861-3Naparus A, Ashrafpour H, Hofer SO, Zhong T, Huang N, Cahoon NJ, et al. Efficacy and mechanism of hypoxic postconditioning in salvage of ex vivo human rectus abdominis muscle from hypoxia/reoxygenation injury. Eur J Pharmacol. 2012;686(1-3):90-6.

PUMA-mediated mitochondrial apoptotic disruption by hypoxic postconditioning. Y Li, Q Guo, X Liu, C Wang, D Song, Apoptosis. 208Li Y, Guo Q, Liu X, Wang C, Song D. PUMA-mediated mitochondrial apoptotic disruption by hypoxic postconditioning. Apoptosis. 2015;20(8):1026-32.

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Gradual reintroduction of oxygen reduces reperfusion injury in cat stomach. M A Perry, S S Wadhwa, Am J Physiol. 2543Pt 1Perry MA, Wadhwa SS. Gradual reintroduction of oxygen reduces reperfusion injury in cat stomach. Am J Physiol. 1988;254(3 Pt 1):G366-72.

Hypoxemic reperfusion after 120 mins of intestinal ischemia attenuates the histopathologic and inflammatory response. E E Douzinas, S Kollias, D Tiniakos, E Evangelou, A Papalois, A D Rapidis, Crit Care Med. 3211Douzinas EE, Kollias S, Tiniakos D, Evangelou E, Papalois A, Rapidis AD, et al. Hypoxemic reperfusion after 120 mins of intestinal ischemia attenuates the histopathologic and inflammatory response. Crit Care Med. 2004;32(11):2279-83.

Myocardial ischemia in intestinal postischemic shock: the effect of hypoxemic reperfusion. E E Douzinas, M T Pitaridis, E Patsouris, S Kollias, V Boursinos, D I Karmpaliotis, Crit Care Med. 318Douzinas EE, Pitaridis MT, Patsouris E, Kollias S, Boursinos V, Karmpaliotis DI, et al. Myocardial ischemia in intestinal postischemic shock: the effect of hypoxemic reperfusion. Crit Care Med. 2003;31(8):2183-9.

Graded postischemic reoxygenation ameliorates inhibition of cerebral cortical protein synthesis in dogs. J Burda, M Marsala, J Radonak, J Marsala, J Cereb Blood Flow Metab. 116Burda J, Marsala M, Radonak J, Marsala J. Graded postischemic reoxygenation ameliorates inhibition of cerebral cortical protein synthesis in dogs. J Cereb Blood Flow Metab. 1991;11(6):1001-5.

The effect of hypoxemic reperfusion on cerebral protection after a severe global ischemic brain insult. E E Douzinas, I Andrianakis, M T Pitaridis, D J Karmpaliotis, E M Kypriades, A Betsou, Intensive Care Med. 271Douzinas EE, Andrianakis I, Pitaridis MT, Karmpaliotis DJ, Kypriades EM, Betsou A, et al. The effect of hypoxemic reperfusion on cerebral protection after a severe global ischemic brain insult. Intensive Care Med. 2001;27(1):269-75.

Hypoxaemic reperfusion ameliorates the histopathological changes in the pig brain after a severe global cerebral ischaemic insult. E E Douzinas, E Patsouris, E M Kypriades, D J Makris, I Andrianakis, P Korkolopoulou, Intensive Care Med. 275Douzinas EE, Patsouris E, Kypriades EM, Makris DJ, Andrianakis I, Korkolopoulou P, et al. Hypoxaemic reperfusion ameliorates the histopathological changes in the pig brain after a severe global cerebral ischaemic insult. Intensive Care Med. 2001;27(5):905-10.

Hypoxemic reperfusion exacerbates the neurological injury sustained during neonatal deep hypothermic circulatory arrest: a model of cyanotic surgical repair. E J Hickey, X You, V Kaimaktchiev, R M Ungerleider, Eur J Cardiothorac Surg. 315Hickey EJ, You X, Kaimaktchiev V, Ungerleider RM. Hypoxemic reperfusion exacerbates the neurological injury sustained during neonatal deep hypothermic circulatory arrest: a model of cyanotic surgical repair. Eur J Cardiothorac Surg. 2007;31(5):906-14.

Hypoxic reoxygenation during initial reperfusion attenuates cardiac dysfunction and limits ischemia-reperfusion injury after cardioplegic arrest in a porcine model. U Abdel-Rahman, P Risteski, K Tizi, S Kerscher, S Behjati, K Zwicker, J Thorac Cardiovasc Surg. 1374Abdel-Rahman U, Risteski P, Tizi K, Kerscher S, Behjati S, Zwicker K, et al. Hypoxic reoxygenation during initial reperfusion attenuates cardiac dysfunction and limits ischemia-reperfusion injury after cardioplegic arrest in a porcine model. J Thorac Cardiovasc Surg. 2009;137(4):978-82.

Graded reoxygenation limits lipid peroxidation during surgical reperfusion. U Abdel-Rahman, T Aybek, A Moritz, P Kleine, G Matheis, Med Sci Monit. 99Abdel-Rahman U, Aybek T, Moritz A, Kleine P, Matheis G. Graded reoxygenation limits lipid peroxidation during surgical reperfusion. Med Sci Monit. 2003;9(9):CR389-91.

Influence of graded postischemic reoxygenation on reperfusion alterations in rabbit dorsal root ganglion neurons. A Fercakova, M Marsala, J Marsala, J Hirnforsch. 352Fercakova A, Marsala M, Marsala J. Influence of graded postischemic reoxygenation on reperfusion alterations in rabbit dorsal root ganglion neurons. J Hirnforsch. 1994;35(2):295-302.

Graded postischemic reoxygenation attenuates ischemia-reperfusion-induced nuclear and nucleolar damage in lumbosacral dorsal root ganglia neurons. A light and electron microscopic study in rabbit. Z Daxnerova, M Marsala, J Marsala, J Hirnforsch. 363Daxnerova Z, Marsala M, Marsala J. Graded postischemic reoxygenation attenuates ischemia-reperfusion-induced nuclear and nucleolar damage in lumbosacral dorsal root ganglia neurons. A light and electron microscopic study in rabbit. J Hirnforsch. 1995;36(3):379-91.

Improvement of energy state and basic modifications of neuropathological damage in rabbits as a result of graded postischemic spinal cord reoxygenation. M Marsala, V Danielisova, M Chavko, A Hornakova, J Marsala, Exp Neurol. 1051Marsala M, Danielisova V, Chavko M, Hornakova A, Marsala J. Improvement of energy state and basic modifications of neuropathological damage in rabbits as a result of graded postischemic spinal cord reoxygenation. Exp Neurol. 1989;105(1):93-103.

The blood-brain barrier permeability in graded postischemic spinal cord reoxygenation in rabbits. J Orendacova, M Marsala, J Marsala, Neurosci Lett. 1282Orendacova J, Marsala M, Marsala J. The blood-brain barrier permeability in graded postischemic spinal cord reoxygenation in rabbits. Neurosci Lett. 1991;128(2):143-6.

Neuroprotective effect of graded postischemic reoxygenation in spinal cord ischemia in the rabbit. N Lukacova, M Marsala, G Halat, J Marsala, Brain Res Bull. 435Lukacova N, Marsala M, Halat G, Marsala J. Neuroprotective effect of graded postischemic reoxygenation in spinal cord ischemia in the rabbit. Brain Res Bull. 1997;43(5):457-65.

Hypoxemic versus normoxemic reperfusion in a large animal model of severe ischemia-reperfusion injury. R K Lehmann, L R Brounts, K E Lesperance, M J Eckert, R N Lesperance, A C Beekley, J Surg Res. 1662Lehmann RK, Brounts LR, Lesperance KE, Eckert MJ, Lesperance RN, Beekley AC, et al. Hypoxemic versus normoxemic reperfusion in a large animal model of severe ischemia-reperfusion injury. J Surg Res. 2011;166(2):194-8.

The effect of hypoxemic resuscitation of hemorrhagic shock on hemodynamic stabilization and inflammatory response: a pilot study in a rat experimental model. E E Douzinas, O Livaditi, A G Xiarchos, E J Giamarellos-Bourboulis, V Villiotou, I A Liappas, J Trauma. 614Douzinas EE, Livaditi O, Xiarchos AG, Giamarellos-Bourboulis EJ, Villiotou V, Liappas IA, et al. The effect of hypoxemic resuscitation of hemorrhagic shock on hemodynamic stabilization and inflammatory response: a pilot study in a rat experimental model. J Trauma. 2006;61(4):918-23.

Stimulation of monocytes is a pathway involved in systemic inflammatory response following haemorrhagic shock resuscitation: the effect of hypoxaemic resuscitation. E E Douzinas, O Livaditi, M K Tasoulis, A Pelekanou, E J Giamarellos-Bourboulis, Clin Exp Immunol. 1503Douzinas EE, Livaditi O, Tasoulis MK, Pelekanou A, Giamarellos-Bourboulis EJ. Stimulation of monocytes is a pathway involved in systemic inflammatory response following haemorrhagic shock resuscitation: the effect of hypoxaemic resuscitation. Clin Exp Immunol. 2007;150(3):502-8.

Hypoxemic resuscitation after hemorrhagic shock is accompanied by reduced serum levels of angiopoietin-2. E E Douzinas, A Betrosian, O Livaditi, K Flevari, T Kanni, M Mouktaroudi, Cytokine. 472Douzinas EE, Betrosian A, Livaditi O, Flevari K, Kanni T, Mouktaroudi M, et al. Hypoxemic resuscitation after hemorrhagic shock is accompanied by reduced serum levels of angiopoietin-2. Cytokine. 2009;47(2):82-4.

Hypoxemic resuscitation prevents pulmonary capillary endothelial dysfunction induced by normoxemic resuscitation from hemorrhagic shock. E E Douzinas, S E Orfanos, O Livaditi, K Augustatou, V Villiotou, N Kavantzas, Crit Care Med. 373Douzinas EE, Orfanos SE, Livaditi O, Augustatou K, Villiotou V, Kavantzas N, et al. Hypoxemic resuscitation prevents pulmonary capillary endothelial dysfunction induced by normoxemic resuscitation from hemorrhagic shock. Crit Care Med. 2009;37(3):869-75.

Hypoxemic resuscitation from hemorrhagic shock prevents lung injury and attenuates oxidative response and IL-8 overexpression. E E Douzinas, A Betrosian, E J Giamarellos-Bourboulis, M K Tasoulis, P Prigouris, O Livaditi, Free Radic Biol Med. 502Douzinas EE, Betrosian A, Giamarellos-Bourboulis EJ, Tasoulis MK, Prigouris P, Livaditi O, et al. Hypoxemic resuscitation from hemorrhagic shock prevents lung injury and attenuates oxidative response and IL-8 overexpression. Free Radic Biol Med. 2011;50(2):245-53.

Nitrosative and oxidative stresses contribute to post-ischemic liver injury following severe hemorrhagic shock: the role of hypoxemic resuscitation. E E Douzinas, O Livaditi, M K Tasoulis, P Prigouris, D Bakos, N Goutas, PLoS One. 7332968Douzinas EE, Livaditi O, Tasoulis MK, Prigouris P, Bakos D, Goutas N, et al. Nitrosative and oxidative stresses contribute to post-ischemic liver injury following severe hemorrhagic shock: the role of hypoxemic resuscitation. PLoS One. 2012;7(3):e32968.

Gradually Increased Oxygen Administration Improved Oxygenation and Mitigated Oxidative Stress after Resuscitation from Severe Hemorrhagic Shock. X Luo, Y Yin, G You, G Chen, Y Wang, J Zhao, Anesthesiology. 1235Luo X, Yin Y, You G, Chen G, Wang Y, Zhao J, et al. Gradually Increased Oxygen Administration Improved Oxygenation and Mitigated Oxidative Stress after Resuscitation from Severe Hemorrhagic Shock. Anesthesiology. 2015;123(5):1122-32.