Evaluation of the Effect of Metformin on the Clinical Outcome of ICU Patients With Sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is considered a life-threatening condition that arises when the body's response to an infection injures its own tissues and organs (Singer et al., 2016a). Organ dysfunction can be defined as an increase in the Sequential (sepsis related) Organ Failure Assessment (SOFA) score more than two points consequent to the infection. A SOFA score more than two points indicates that an overall mortality risk of approximately 10% in hospital population with suspected infection.(Singer et al., 2016b). Septic shock is defined as subset of sepsis in which circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP (mean arterial pressure) more than or equal 65mmHg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation (Seymour et al., 2016).

Sepsis and septic shock are major healthcare problems, affecting millions of people around the world each year with a mortality rate between one in three and one in six of those it affects (Evans et al., 2021). According to a meta-analysis conducted in 2020, it was found that the incidence of sepsis was 189 hospital-treated sepsis cases per 100,000 person-years with a 26.7% mortality rate. In ICU patients, the incidence was 58 per 100,000 person-years with a mortality rate of 41.9% prior to hospital discharge (Fleischmann-Struzek et al., 2020).

The pathogenesis of sepsis is very complicated as it involves imbalance in inflammatory response, immune dysfunction, mitochondrial damage, coagulopathy, neuroendocrine immune network abnormalities, endoplasmic reticulum stress, autophagy, and other pathophysiological processes, and leads to organ dysfunction. Inflammatory Imbalance represents the most critical basis of sepsis pathogenesis. The host's initial acute response to invasive pathogens causes macrophages to engulf the pathogens and produce a range of pro-inflammatory cytokines, and this can trigger cytokine storms and activate the innate immune system. The activation of the innate immune system is mediated by pattern-recognition receptors (PRRs), which initiate a series of activation in immune cells by detecting damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), and thus upregulate the expression of inflammation related genes. In the immune response to sepsis, both exogenous factors derived from the pathogen (e.g., lipopolysaccharide (LPS)) and endogenous factors released by injured cells (e.g., high-mobility group box-1 (HMGB-1) protein) can interact with various PRRs, such as Toll-like receptors (TLRs), which leads to the activation of several pathways including p38 mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling pathways. These events are followed by the production of inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), interferon (IFN) regulatory factor 7 (IRF7), and adaptor protein 1 (AP-1) (Huang, Cai and Su, 2019).

Moreover, studies have also shown that in early stages of sepsis, exaggerated endothelial activation, vascular leakage, disturbance of blood flow, as well as other derangements cause the loss of vascular integrity, which contributes significantly to sepsis-associated organ failure. Therapies interfering endothelial activation are potential to attenuate sepsis-induced organ dysfunction (Tian et al., 2019) Sepsis is associated with many biochemical abnormalities that is correlated with patients' prognosis and risk of mortality including increased levels of lactate, procalcitonin and inflammatory cytokines as TNF alpha.(Cho and Choi, 2014) Despite great efforts was done to understand the pathogenesis of sepsis and investigate therapeutic strategies, the management of sepsis remains a clinical challenge (Tian et al., 2019). Till current date the pathogenesis of sepsis is not completely clear but most of the studies suggested that the release of inflammatory factors by patient's innate immune cell plays an important role in the disease progression (Liang et al., 2019). Recently several studies revealed the anti-inflammatory effect of some drugs in sepsis. One of the drugs that showed anti-inflammatory effect in these studies is metformin (Han et al., 2018).

Metformin is an oral anti-diabetic drug from the class of biguanides. It is the first line treatment of diabetes type 2. It is widely used as it has good safety profile, low side effect and cheap cost (Malik et al., 2018). Studies have shown that metformin modulates cellular metabolism by two inter-related mechanisms. It transiently inhibits mitochondrial complex I of the electron transport chain, decreasing the production of mitochondrial reactive oxygen species and complex I inhibition also leads to an increase of the adenosine monophosphate/adenosine triphosphate (ATP) ratio (a critical signal of energy imbalance), which activates the AMPK. AMPK is a ubiquitous, critical cellular energy sensor with pleiotropic effects on cell metabolism, which can protect the cell by shutting down ATP consuming processes, promoting fatty acid oxidation and controlling the turn-over cycle of injured mitochondria. Metformin and AMPK activation improve endothelial function, reducing capillary leak and inducible nitric oxide synthase and increasing endothelial nitric oxide synthase activity potentially improving vascular tone and microvascular function (Gómez et al., 2022) Metformin has been reported to have an anti-inflammatory effect. In a prospective study to investigate the anti-inflammatory effect of AMPK activation in vivo, metformin and AICAR was administered respectively to mice prior to LPS injection. LPS injection significantly increased the level of VCAM1 in the arterioles, peritubular capillaries, post capillary venules, and glomerulus in the kidneys as well as in the arterioles, alveolar capillaries, and venules in the lungs. Metformin and AICAR administration effectively reduced VCAM1 expression in the microvascular beds both in the kidneys and lungs. Furthermore, LPS-induced increase of the serum levels of pro-inflammatory cytokines TNF⍺ and IL-6 were both significantly decreased by metformin and AICAR (Tian et al., 2019). In a trial of patients receiving glucocorticoid treatment for various chronic inflammatory diseases, 12 weeks of treatment with metformin 2550 mg/day resulted in lower serum levels of high-sensitive CRP as compared to placebo. Furthermore, carbohydrate-challenged TNF-α levels increased significantly in the placebo-treated group but not in the metformin-treated group (Pernicova et al., 2020) In addition, metformin showed some antibacterial activity. A retrospective study conducted in 2022 has shown that at the cellular level, metformin modulates cell metabolism through transient inhibition of complex I of mitochondrial electron transport chain and activates AMPK that protects energy balance in the cell (Gómez et al., 2022). It enhances neutrophil chemotaxis and phagocytosis and bacterial clearance (Bai and Chen, 2021).