Current Concepts in Sepsis

Purpose: e purpose of this review is to consider the state of oxidative stress, failure of the antioxidant systems and mitochondrial failure as the main physiopathological mechanisms leading to multiple organ dysfunction during sepsis. Principal ndings: Sepsis is a clinical syndrome caused by a severe infection that triggers an exaggerated in ammatory response. Involved in the pathogenesis of sepsis are the activation of in ammatory, immune, hormonal, metabolic and bioenergetic responses. One of the pivotal factors in these processes is the increase of reactive species accompanied by the failure of the antioxidant systems, leading to a state of irreversible oxidative stress and mitochondrial failure. In a physiological state, reactive species and antioxidant systems are in redox balance. e loss of this balance during both chronic and infectious diseases leads to a state of oxidative stress, which is considered to be the greatest promoter of a systemic in ammatory response. e loss of the redox balance, together with a systemic in ammatory response during sepsis, can lead to progressive and irreversible mitochondrial failure, energy depletion, hypoxia, septic shock, severe sepsis, multiple organ dysfunction and death of the patient. Conclusion: Knowledge of the molecular processes associated with the development of oxidative stress should facilitate the development of e ective therapies and better prognosis for patients with sepsis and organ dysfunction. REVIEW ARTICLE © 2014 CIM Clin Invest Med • Vol 37, no 2, April 2014 E58 Correspondence to: Jose na Duran-Bedolla Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública. Av. Universidad #65. Col. Santa María Ahuacatitlán, Cuernavaca, Morelos, México. E-mail: jose [email protected] Manuscript submitted 3rd December, 2013 Manuscript accepted 27th January, 2014 Clin Invest Med 2014; 37 (2): E58-E69. Current Concepts in Sepsis Sepsis is an excessive or poorly regulated systemic in ammatory response that causes intravascular damage in the host. It is diagnosed by clinical evidence of infection (suspected or documented) and at least two parameters that indicate a systemic in ammatory response [1, 2] (In ammatory variables, Table 1). Severe sepsis is associated with the dysfunction of one or more organs, and is characterized by hyperlactatemia, oliguria, altered mental status, arterial hypoxemia, arterial hypotension and hyperglycemia [1] (Organ dysfunction variables, Table 1). Septic shock is produced by the presence of sepsis with refractory hypotension (Figure 1). It is de ned as systolic blood pressure (SBP) <90 mmHg, mean arterial pressure (MAP) <70 mmHg, or a decrease in SBP of >40 mmHg in adults or less than two standard deviation below normal according to age, despite adequate uid resuscitation [3, 4] (Hemodynamic variables, Table 1). Septic shock can be understood as severe sepsis with cardiovascular failure. With septic shock, there is a decrease in blood perfusion and supply of oxygen to cells. As is amply demonstrated, cellular hypoxia causes an increase of free radicals, which increases the already high state of oxidative stress and leads to the entry of calcium to the endoplasmic reticulum and mitochondria, causing the release of cytochrome c and the induction of cellular death. Finally, mitochondria failure with the consequent energy de cit does not allow for normal cellular metabolism [5]. With ischemia, the accumulation of intracellular calcium leads to an increase of AMPc and vascular endothelium injury [6]. In ammation, manifested clinically as the systemic in ammatory response syndrome (SIRS) is a prerequisite for the development of sepsis. SIRS is a progressive systemic in ammatory response to infection or some non-infectious process. us there is a close relationship between oxidative stress and the in ammatory response in septic shock. It has been shown that in ammation causes a state of oxidative stress; therefore, SIRS, together the hypoxia present in septic shock, induces a state of oxidative stress with irreversible mitochondrial failure causing organ dysfunction. is condition is characterized by the progressive dysfunction of two or more systems (Figure 1). Finally, two major factors lead to multiple organ dysfunction during sepsis: 1) SIRS, which is characterized by an inammatory response that produces free radicals, thus increasing the state of oxidative stress and 2) failure of cellular perfusion, which leads to hypoxia and produces a large quantity of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cells, leading to mitochondrial failure, to multiple Durán-Bedolla et al. Sepsis, mitochondrial failure and MOD © 2014 CIM Clin Invest Med • Vol 37, no 2, April 2014 E59 TABLE 1. Diag nostic criteria of sepsis.