Ischemia-reperfusion is characterized by blood supply restriction followed by restoration ^[1][5]. Ischemia reduces oxygen and nutrient supply, which is initially compensated for by a reduction in the systemic metabolic rate ^[2][6]; however, a sustained ischemic process leads to cell damage.

Oxygen deprivation impairs mitochondrial oxidative phosphorylation, shifting energy production to anaerobic metabolism, which generates tissue acidosis. Acid–base imbalance is responsible for several cellular dysfunctions. Energy stores are finite; once they are depleted, there is a failure of active cellular processes, such as the regulation of membrane ion pumps, resulting in electrolyte imbalance and, for example, sodium and water accumulation. These processes cause cell edema, calcium influx (which acts as a second messenger of several injury cascades via mitochondrial damage), changes in gene expression, and increased production of reactive oxygen species ^[3][4][5][6][7,8,9,10].

Tissue injury triggers the activation of inflammatory cascades. This activation can be beneficial by promoting tissue repair, or it can be harmful by triggering uncontrolled inflammation, perpetuating tissue damage. When inflammatory activation is harmful, it has a similar profile to that observed in sepsis, which is characterized by a high concentration of cytokines, although it usually occurs in a sterile environment ^[7][11]. A study on the plasma of patients after CA showed that it induced more in vitro endothelial cell death compared with plasma of septic shock patients, reinforcing its toxic character ^[8][12].

Inflammatory activation occurs in the ischemic period and during reperfusion. The mechanism for this involves innate and adaptative immune systems and the complement system. The innate system is activated by endogenous molecules called damage-associated molecular patterns, which are generated or released during cell injury ^[9][10][13,14]. Especially during the initial phase of reperfusion, innate immune cells are preponderant in inflammatory infiltrates ^[1][5]. The adaptative immune system is responsible for the activation of T lymphocytes and their products, which can cause tissue damage ^{[11][12][13][14]}[15,16,17,18]. Humoral activation also contributes to further tissue damage. Finally, the complement system acts by differentiating healthy tissue from cellular debris and apoptotic and intruding cells ^[15][19]; it is activated by locally amplifying the inflammation. A detailed description of the inflammatory pathways activated at each moment of ischemia-reperfusion syndrome (IRS) is beyond the scope of this rentry, but  view, but we would like to emphasize the importance of inflammation should be emphasized.

Another IRS component is endothelial dysfunction. Endothelial tissues are among the most vulnerable to IR-induced injury ^[16][20]; damage thereof causes increased vascular permeability, hypercoagulability, vasoconstriction, and local inflammation ^[17][18][21,22]. The main stimulus for increased vascular permeability is the hypoxemia which occurs in the ischemic period ^[19][23]. Hypercoagulability occurs by platelet activation and by endogenous pro- and anticoagulant factors that result in an imbalance that can culminate in disseminated intravascular coagulation ^[20][24]. Regarding vasomotor tone, vasoconstricting substances predominate independently of smooth muscle function ^[21][25]. Vasoconstriction endothelial mechanisms are described in fully denervated transplanted hearts ^[22][26]. Additionally, endothelial dysfunction stimulates an inflammatory response including leukocyte recruitment, complement activation, and pro-inflammatory gene expression ^[23][27].

Regarding reperfusion injury, blood flow restoration is essential but deleterious. The supply of oxygen promotes the generation of free radicals (FR) ^[24][28], highly reactive molecules which have an unpaired electron and interact with nearby structures to achieve electrical stability. The most well-known examples include superoxide anions, hydrogen peroxide, and hydroxyl radicals. They are produced by neutrophils, eosinophils, and endothelial cells in various cellular processes ^[25][29]. FR can cause peroxidation of membrane fatty acids, enzyme inactivation, deoxyribonucleic acid (DNA) modifications, activation of inflammatory messengers, platelet induction, nitric oxide inactivation, and the release of vasoconstrictor agents, among other things. FR-induced lesions are called oxidative stress ^[24][26][28,30]. Under normal conditions, endogenous protective mechanisms (antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase) and FR scavengers (glutathione, α-tocopherol, and β-carotene) control oxidative damage ^[27][31]. However, in IRS, FR production overcomes the protection mechanisms, as already demonstrated in PCA patients ^[28][32].

In summary, the pathological processes was described above, i.e., hypoxemia, endothelial injury, platelet activation, inflammation, and reperfusion-induced injury, are closely related to each other, ultimately culminating in cell death. Initially, there were only two known pathways of cell death: apoptosis and necrosis. Necrosis is defined as uncontrolled cell death that damages adjacent structures by releasing cell contents and inflammation, while apoptosis represents a controlled form of cell death with minimal effect on the surrounding tissue and without leakage of cell contents, conferring a silent and anti-inflammatory character ^[29][33]. However, as studies have progressed, other pathways of cell death have been identified, such as autophagy, necroptosis, ferroptosis, and pyroptosis ^[30][34]. Each of these mechanisms is activated by distinct signaling pathways, culminating in different modes of cell death and different consequences for the organism ^[31][35].

Regardless of the predominant pathway, the classical mechanisms of injury that result in cell death include reduced adenosine triphosphate (ATP) synthesis ^[32][36], irreversible mitochondrial injury, and alteration of calcium homeostasis ^[33][37]. These processes result in the activation of enzymes such as phospholipases (causing damage to the membrane), proteases (which degrade the membrane and cytoskeleton), ATPases (which degrade ATP), and endonucleases (which degrade DNA), as well as oxidative stress and the loss of genome integrity ^[30][34].

Neurological outcome is one of the main determinants of PCA survival, representing an important cause of mortality and morbidity ^[34][38]. Brain injury can be catastrophic. The central nervous system (CNS) does not have its own metabolic stores and is highly dependent on oxygen, being responsible for 20% to 25% of total body oxygen consumption ^[35][4].

In primary injury, there is a deficit of supplements, calcium dyshomeostasis ^[33][37], mitochondrial dysfunction ^[36][37][40,41], oxidative stress ^[38][39][42,43], inflammatory activation ^[40][41][42][44,45,46], and excitotoxicity. Secondary injury is caused by microvascular dysfunction, cerebral edema, oxygen and carbon dioxide concentrations, hyperthermia, anemia, hyperglycemia, and seizures.

Microvascular dysfunction results from microthrombi, vasoconstriction, and disruption of the blood–brain barrier, resulting in increased vascular resistance, reduced blood flow, and edema. Cerebral edema is vasogenic and cytotoxic. The former is mainly mediated by aquaporins which cause fluid displacement in the interstitium. Cytotoxicity occurs due to energy depletion and dysregulation of membrane ion pumps, leading to intracellular sodium and water retention. Regardless of the mechanism, edema occurs in a fixed volume system and, therefore, the volumetric increase in the parenchyma causes intracranial hypertension, reduced perfusion, and even cerebral herniation ^[43][47].

Hypoxemia is deleterious to neuronal function, but hyperoxia is also harmful because FR production increases. Thus, it is important to maintain strict control of oxygen concentrations ^[44][48]. Carbon dioxide modulates vasomotor tone, interfering with blood flow and intracranial pressure. Hypercapnia and hypocapnia induce, respectively, vasodilation and vasoconstriction. Anemia reduces arterial oxygen content, contributing to ischemia. The arterial oxygen content is primarily dependent on hemoglobin ^[45][49]. Hyperthermia increases metabolic oxygen demand, reduces seizure threshold, and induces apoptosis, causing cell death. Hyperglycemia is associated with poor neurologic outcomes after CA, and studies have linked glycemic control with PCA survival ^[46][47][50,51]. Seizures are associated with a worse neurological prognosis and death. This manifestation is a cause and a consequence of PCA brain injury and increases brain metabolism by up to three times ^[48][52].

Another particularity of brain tissue is its limited tolerance of ischemia. The oxygen deprivation time required for the onset of cellular damage in the CNS is shorter than in other tissues ^[49][50][53,54]. Despite the early onset of brain injury, evidence has shown an increase in injury cascades up to 7 days after reperfusion, probably due to secondary injury mechanisms, providing a wide therapeutic window for neuroprotective strategies after CA ^{[51][52][53][54]}[55,56,57,58].

Post-ischemic myocardial dysfunction was first described in the 1970s ^[55][59], and in 1982, it was consolidated as a clinical entity by Braunwald and Kloner ^[56][60]. The incidence of myocardial dysfunction can reach 68%, usually causing early and intense dysfunction that can be completely reversed after 48–72 h ^[57][58][61,62].

Cardiac dysfunction affects systole and diastole. Systolic deficit is demonstrated by reduced global contractility, cardiac index, and ejection fraction ^[59][63]. Studies have shown a difference of up to 14% in the ejection fraction of patients with and without myocardial dysfunction after CA ^[58][62]. Diastolic deficit occurs as an extension of ischemic contracture by uncontrolled activation of the contractile machinery, increased rigidity, and decreased myocardial compliance ^[60][64]. The severity of ischemic contracture is proportional to the duration of ischemia and is maximal during the metabolic phase (after about 10 min) of CA ^[61][65]. The repercussions include ventricular wall thickening, deficient relaxation, and reduced end-diastolic volume ^[60][62][64,66]. A common pathway of systolic–diastolic injury that is worth mentioning is cardiac edema; this occurs due to reduced lymphatic flow, a consequence of the loss of rhythmic contraction, and to increased microvascular permeability. Studies indicate that a 3.5% gain in myocardial water results in a 30–50% decline in cardiac output ^[63][67].

Another myocardial particularity is metabolic and electrical status. The heart’s main energy source is the oxidation of fatty acids, providing 60–70% of its energy needs ^[64][68]. However, after critical ischemia, glucose dominates as the energy source because lipid oxidation, despite being more effective, consumes more oxygen. As a consequence of this metabolic deviation, there is less ATP production and potentially an accumulation of toxic lipid substances, causing myocyte apoptosis, myocardial fibrosis, and, ultimately, cardiac dysfunction ^[65][69]. In contrast, when reperfusion takes place, lipids once again become the main energy source, and oxygen consumption increases, also leading to cardiac dysfunction ^[66][70]. Regarding cardiac electrical potential, IRS can interfere with myocardial electrical control. Energy depletion, ionic imbalance, and the presence of reactive oxygen species destabilize cardiac electrical activity, causing membrane depolarization, shortening the potential of action, and stimulating arrhythmic activity ^[60][67][64,71]. Ventricular premature beats, ventricular tachycardia, and episodes of fibrillation may occur, especially in the first 5 to 20 min after ROSC ^[68][72].

CPR can also contribute to myocardial injury, initially directly due to chest compressions ^[69][73], but also due to exogenous factors such as the administration of epinephrine, which, by β-adrenergic stimulation, increases oxygen consumption and the probability of arrhythmias ^[70][74], while electric shocks produce cell injury proportional to the amount of energy used ^[71][75]. In addition, CPR can also cause reperfusion injuries, because the coronary blood flow during resuscitation is low and does not maintain aerobic myocardial metabolism; however, it is sufficient to promote the deleterious effects of reperfusion ^[72][76].

Respiratory dysfunction occurs in up to 50% of patients. It may be caused by pulmonary edema, contusion, or atelectasis. Persistent vasoconstriction causes loss of self-regulation of blood flow to the kidneys, reducing glomerular filtration and promoting a pro-inflammatory state due to endothelial damage that can perpetuate the mechanisms of renal injury ^[73][74][77,78]. Gastrointestinal tract (GIT) insult is often underestimated due to the difficulty of assessment. However, in addition to being a victim of circulatory failure, the GIT perpetuates the systemic inflammatory response, because a loss of barrier integrity favors the systemic translocation of endotoxins ^[2][6]. GIT injury occurs especially in the reperfusion period. Injuries induced by three hours of ischemia followed by one hour of reperfusion are more severe than those induced by four hours of ischemia alone ^[75][79]. The liver is a resistant organ with unique protection mechanisms against ischemia, such as double irrigation (portal vein and hepatic artery), high permeability of the hepatic sinusoids (favoring diffusion and allowing an increase of up to 90% in the extraction of available oxygen ^[76][77][80,81]), and great glycolytic capacity to generate ATP in the absence of oxygen. Even so, liver injury is still observed in around 24% of cases and is strongly associated with mortality and worse neurological outcome in victims of CA ^[78][82]. Finally, adrenal dysfunction due to direct glandular damage to the hypothalamic–pituitary–adrenal axis can reduce the release of catecholamines and corticosteroids ^[79][83].