Efficacy and Safety of Oral Nicotinamide as an Adjunctive Therapy in Patients With Sepsis

Sepsis is a life-threatening medical illness caused by the body's response to an infection, resulting in extensive inflammation. This inflammation can cause a series of changes in the body, leading to restricted blood flow to key organs, causing organ failure and eventually death. Sepsis can be caused by bacteria, viruses, fungi, or parasites, or it can develop due to noninfectious intra-abdominal causes, including severe trauma, pneumonia, pancreatitis, and urinary system infection. Despite advances in medical treatments, sepsis remains a major cause of death globally among hospitalized patients because of its complications. According to reports, Hospital mortality rates were 26% for hospital-wide sepsis and 40% for ICU sepsis. Sepsis was more common in the United States among men, non-white individuals, and the elderly (60 years and older) than among women and white persons.

Severe sepsis is characterized by one or more end-organ failures, while septic shock is characterized by hemodynamic instability despite intravascular volume replacement. The overwhelming immune response and the altered balance between pro-inflammatory and anti-inflammatory mediators contribute to the development of sepsis, making it particularly challenging to treat.

Some possible complications of sepsis include Acute/chronic renal injury, Mesenteric ischemia, Acute liver failure, Myocardial dysfunction, and Multiple organ failure. Previous studies showed that sepsis can cause the disturbance of immunological homeostasis, leading to immunosuppression in sepsis.

The SOFA (Sequential Organ Failure Assessment) score is currently advised for diagnosing both sepsis and septic shock. A diagnosis of sepsis is confirmed in the case of a (SOFA) score ≥ 2. The SOFA system is a simple technique that detects organ failure or dysfunction due to sepsis. Daily, the SOFA scoring scale allocates from 1 to 4 points for each of the following six organ systems, according to the level of dysfunction: The respiratory, circulatory, renal, hematological, hepatic, and central nervous systems. Sepsis is presented by a rise of two or more points in the SOFA score. Moreover, the SOFA score could be a method to assess morbidity in intensive care unit (ICU) sepsis patients.

Cytokines are essential for the effective functioning of critical host immune systems because they regulate the body's reactions to infection, immunological responses, inflammation, and trauma. Modifying the cytokine response is an important aspect of therapy for many severe inflammatory disorders. In septic patients, it has been demonstrated that TNFα, IL-6, and IL-1β correspond with the severity of the disease and its outcome.

Oxidative stress (OS) damage plays a role in the pathogenesis of major disorders such as sepsis-induced multiple organ failure (MOF). Studies in animal models and septic shock patients have revealed an imbalance between the formation of reactive oxygen (ROS) and nitrogen (RNS) species and antioxidant defenses. ROS are produced by phagocytic cells, enzymes such as NADPH oxidase, xanthine oxidase, and iNOS, and enhanced inflammatory mediators via NFκB activation. OS-induced mitochondrial damage is part of the pathogenesis of MOF, subsequent sepsis.

To diagnose sepsis patients: SOFA score ≥ 2, mean arterial pressure (MAP) \< 65 mmHg, and serum lactate level ≥ 2 mmol/L. Blood should be collected before initiating antibiotics to guide therapy and help determine the source of infection.

Effective sepsis management requires a combination of rapid interventions and supportive care. It involves different pathophysiological aspects, encompassing empirical antimicrobial treatment (which is promptly administered after microbial tests), fluid (crystalloids) replacement (to be established according to fluid tolerance and fluid responsiveness), and vasoactive agents (e.g., norepinephrine). Administering the appropriate medications on time has been linked to higher survival rates. Supportive care and adjuvant therapy, such as the use of corticosteroids, blood purification techniques, and immunomodulatory therapies, are still under investigation.

The inflammatory response in sepsis has played a significant role, and so, Standard therapy includes the use of steroidal and non-steroidal anti-inflammatory medicines, which have resulted in poor outcomes. Currently, antioxidant therapy in septic shock patients has been demonstrated to be effective in lowering Oxidative Stress (OS) indicators. Similarly, it was discovered that adding antioxidant therapy to the standard therapy in septic shock enhances total antioxidant capacity and reduces OS.

Many therapeutic strategies have focused on controlling the inflammatory response and managing oxidative stress, both of which are central to sepsis pathogenesis. Antioxidants and anti-inflammatory medications aim to counteract the overproduction of reactive oxygen species (ROS) and inflammatory cytokines, potentially reducing damage to tissues and organs. However, the complexity of sepsis, with its multifactorial nature and diverse responses among patients, continues to present challenges for developing more effective treatments.

Patients who receive antioxidants such as vitamin C, vitamin E, NAC, or MT in addition to traditional therapy demonstrate lower levels of pro-inflammatory cytokines and enhanced regulatory function in IL-2, IL-12, and IFN. The antioxidant capacity has improved, and indicators of oxidative stress have decreased, indicating that organ damage has reduced as determined by the SOFA score.

Nicotinamide (or nicotinamide) is a form of vitamin B3 that is often confused with its precursor nicotinic acid (or niacin) . Nicotinamide (NAM; niacin), nicotinic acid (niacin), and NAM riboside (NR) are the three vitamins that make up the components of the water-soluble vitamin B3 family. Nicotinamide is a precursor to two essential cofactors in cellular metabolism: Nicotinamide adenine dinucleotide (NAD) and its phosphate form, NADP. Nicotinamide adenine dinucleotide (NAD+) coenzymes are the primary regulators of cellular metabolism. While metabolic stress and age-related diseases can disrupt the NAD+ system, NAD is essential for several biological functions, such as DNA repair, energy synthesis, and cellular stress mechanisms.

Previous research suggests that NAM can effectively reduce cytokine release and inflammatory cell chemotaxis in skin disorders. Research indicates that NAM can reduce the number of inflammatory macrophages in chemically induced skin cancer. NAM has been shown to inhibit the secretion of cytokines and the chemotaxis of inflammatory cells in inflammatory skin diseases. This suggests that NAM might play a role in modulating immune responses, especially in conditions where excessive inflammation leads to tissue damage, like in psoriasis or eczema.

NAM may have therapeutic potential as a modulator of cytokine effects in inflammatory diseases since it significantly inhibits the proinflammatory cytokine response of IL-1β, IL-6, IL-8, and TNFα after endotoxin stimulation of human whole blood.

In general, Nicotinamide has fewer potential negative effects than other niacin supplements. There are expected mild side effects of NAM as (gastrointestinal upset, Headache, dizziness and Fatigue). However, a medication safety trial reported that consuming larger amounts of Nicotinamide than usual can increase the likelihood of adverse effects, such as diarrhea, increased liver enzymes (rarely occurring at doses exceeding 3 grams per day), symptoms of thrombocytopenia (including increased bruising and bleeding), which is a rare side effect. The severity of nicotinamide-induced adverse effects determines how they are managed. Antacids such as calcium carbonate, probiotics, or taking the dose with food can help ease gastrointestinal distress. Headaches can be treated with basic analgesics such as paracetamol or ibuprofen if not contraindicated. Although dizziness normally requires just supportive care, such as appropriate fluids or oral rehydration, it may be needed. Fatigue has no specific pharmacologic treatment, but improving sleep, staying hydrated, and taking a non-excessive B-complex supplement may assist. Diarrhea caused by large doses can be treated with oral rehydration salts and, if necessary, short-term loperamide, as well as lowering the nicotinamide dose.

Nicotinamide riboside (NR) increases NAD+ + levels and may help lower inflammation, even if metabolic stress and age-related disorders dysregulate the NAD+ + system. A previous Study Proves that NR markedly reduced the gene expression of IL-6 and IL-18 in peripheral blood mononuclear cells Moreover, it was found to reduce the incidence of RRT/death and improve the creatinine outcome in individuals with severe COVID-19-related AKI. Larger randomized trials are required to determine a causal link Given the high morbidity and mortality associated with septic patient, incorporating NAM as an adjunct to standard sepsis care could offer a novel therapeutic approach to improving survival and reducing long-term complications.

• Change in IL-6 levels in serum [Time frame: At the 7th day of follow up]
• Change in NF-kB in serum [Time frame: At 7th day of follow up]
• Length of ICU stay (days) [Time frame: From ICU admission until ICU discharge or death, up to 28 days]
• 28 day Mortality [Time frame: At the 28th day of follow up]
• Length of hospital stay (days) [Time frame: From hospital admission until discharge, up to 28 days]
• Assess the septic patients Mortality rate. [Time frame: 28 mortality day]