The Effect of Montelukast Versus Co Enzyme Q10 on the Clinical Outcome of Patients With Sepsis

Sepsis is now defined as a life-threatening organ dysfunction linked to a dysregulated host response to infection. This organ dysfunction can be identified using the Sequential Organ Failure Assessment (SOFA). Sepsis is a leading cause of morbidity and mortality in the intensive care unit (ICU). It has been reported that the short-term mortality rate ranges from 30 to 50%, depending on illness severity. The global epidemiological burden of sepsis is, however, difficult to ascertain. It is estimated more than 30 million people are affected by sepsis every year worldwide, resulting in potentially 6 million deaths annually. The mortality rate estimated to be 30% in sepsis and 80% in septic shock in the USA, and 12.8% in sepsis and 45.7% in septic shock in Europe. Reduced rates of reporting may influence estimations in developing countries.

Sepsis is characterized by overwhelming systemic inflammation causing a release of proinflammatory cytokines. The presence of infection leads to initial activation of the innate immune response. The resulting pro-inflammatory host response is both complex and redundant, involving many soluble inflammatory mediators, including cytokines [e.g., tumor necrosis factor (TNF) α and interleukin (IL) 6] and reactive oxygen/nitrogen species (e.g., nitric oxide (NO) and peroxynitrite), as well as multiple cell types, including neutrophils, macrophages, platelets, and endothelial cells. The up regulation of pro- and anti-inflammatory pathways leads to a system-wide release of cytokines, mediators, and pathogen-related molecules, resulting in activation of coagulation, and complement cascades, the resulting inflammation leads to progressive tissue damage, finally causing multi-organ dysfunction.

Sepsis-induced mitochondrial damage or dysfunction can result in cellular metabolic disorders, insufficient energy production, and oxidative stress, which give rise to the apoptosis of organ cells and immune cells, thus ultimately generate immune disorders, multiple organ failure, and even death. As during sepsis limited amount of oxygen supply, the free radical production increases dramatically while the machinery of the antioxidant system becomes damaged. Activated leukocytes release inflammatory cytokines, which trigger overproduction of reactive nitrogen species (RNS) and nitrogen oxide. Nitrogen oxide can bind to reactive oxygen species (ROS) peroxides to form RNS, which unfortunately brings about further damage to mitochondria, including mitochondrial, and mitochondrial DNA damage.

Hence, different treatment strategies have focused in minimizing this inflammatory syndrome without reaching a consensus. Numerous anti-inflammatory and antioxidants therapies have been proposed and studied, including corticosteroids, anti-cytokine approaches, selenium, vitamin C, as well as other various basic research-driven therapies.

Montelukast is a cysteinyl leukotriene receptor antagonist with anti-inflammatory and antioxidant properties. Cysteinyl leukotrienes (CysLTs) are formed by inflammatory cells, such as mast cells, eosinophils, and basophils. CysLTs are potent pro-inflammatory mediators that increase microvascular permeability and are effective chemotactic agents. CysLT receptors are present in the airways, liver, and other organs. CysLT1 antagonists, such as Montelukast, have been reported to ameliorate experimental colitis, burn- and sepsis-induced multi-organ damage. Montelukast acts by inhibiting neutrophil infiltration, balancing oxidant-antioxidant status, and controlling inflammatory mediator generation. Montelukast possesses anti-inflammatory effect through the inhibition of TNF-alpha stimulated by IL-8 expression through changes in nuclear factor-Kb, and the antioxidant effect is due to decreasing the ROS, and reactive nitrogen species (e.g. NO) production, and hence it could help ameliorate inflammation associated with sepsis.