The Effect of Melatonin on Thrombosis, Sepsis and Mortality Rate in COVID-19 Patients

Abstract

The purpose of this study is to determine the effect of melatonin on thrombosis, sepsis, and mortality rate in adult patients with severe coronavirus infection (COVID-19).

Methods:

This single-center, prospective, randomized clinical trial was conducted from 1 December 2020 to 1 June 2021 at Al-Shifaa hospital in Mosul, Iraq. There were 158 patients with severe COVID-19 included in the study, 82 in the melatonin group (who received 10 mg melatonin in addition to standard therapeutic care), and 76 in the control group (given standard therapeutic care only). Patients were chosen by blocked randomization design. The physician then evaluated and recorded the incidence of thrombosis, sepsis, and mortality rate on days 5, 11, and 17 of symptoms.

Results:

The intervention group consisted of 82 patients, while the control group consisted of 76 patients. In comparison to the control group, thrombosis and sepsis developed significantly less frequently (P < 0.05) in the melatonin group during the second week of infection, while mortality was significantly higher in the control group (P < 0.05).

Conclusions: Adjuvant use of Melatonin may help reduce thrombosis, sepsis, and mortality in COVID-19 patients.

https://www.sciencedirect.com/science/article/pii/S1201971221007980

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Discussion:

Worldwide, the COVID-19 pandemic has infected and killed millions of people. These large numbers necessitate a rapid development of clinical trials evaluating therapies capable of lowering the alarmingly high death rate. As a result, a large number of drugs have been studied in COVID-19 patients. Melatonin's efficacy as an adjunctive therapy has been demonstrated in a variety of diseases (Biancatelli RMLC, et al. 2020; Zhang R, et al. 2020). There are, however, few trials evaluating the use of melatonin in patients with COVID-19 (Gholamreza, et al. 2020; Ali Ameri, et al. 2021; Miguel Rodriguez-Rubio, et al. 2021), while our study is randomized trial evaluating the efficacy and safety of 10 mg oral melatonin as an adjunctive therapy in patients hospitalized with severe COVID-19. It has been well found that melatonin administration could alleviate viral infection-induced oxidative stress as well as increasing the antioxidant activity (Habtemariam S, et al. 2017). In the current study three clinical complications (Thrombosis, sepsis & mortality rate) were evaluated.

Effect of Melatonin on Thrombosis in COVID-19 Patients:

Coronaviruses have been shown to enter cells via angiotensin-converting enzyme 2 (ACE-2) receptors, which are predominantly found on the alveolar epithelium and endothelium. Endothelial cell activation is thought to be the primary cause of thrombosis. Inclusion bodies from viruses have been identified in endothelial cells from a variety of organs, including the lung and gastrointestinal tract (Varga Z, et al. 2020). Rapid viral replication results in the release of large amounts of inflammatory mediators. One theory proposed that neutrophil extracellular traps (NETs) could be the source of hypercoagulation in severe COVID-19 patients. High NET levels in the blood are associated with elevated thrombin levels, which are predictive of adverse cardiac events that can result in major organ damage (Barnes BJ. Et al. 2020). In severe cases of COVID-19, a retrospective analysis of 452 patients revealed a significant increase in neutrophil counts (Qin C, et al. 2020). NETs have the ability to alter endothelial barrier structures, resulting in an increase in vascular endothelial permeability and a decrease in anti-thrombotic and anti-inflammatory properties (Ma Y, et al. 2019; Hernández-Reséndiz S, et al. 2018). Local injection of melatonin (140 pg) into endothelial cells effectively reduced endothelial cell vascular permeability induced by leukotriene B4-activated neutrophils, as demonstrated in an in vivo rodent experiment. Melatonin's inhibition of endothelial cell hyper-adhesiveness likely mediated the decrease in vascular permeability (Lotufo CM, et al. 2006). In 46 healthy young men, oral melatonin (3 mg) administration resulted in an inverse relationship between procoagulant measures, with increased plasma melatonin predicting lower FVIII:C (P = 0.037) and fibrinogen (P = 0.022) levels (Wirtz PH, et al. 2008).

The increased D-dimer level is one of the most consistent findings. Although numerous inflammatory processes can affect D-dimer levels, they almost certainly reflect intravascular thrombosis to some extent in patients with COVID-19 (Leonard-Lorant I, et al. 2020; Cui S, et al. 2020). An elevated D-dimer level (>1000 ng/mL) at admission was associated with an increased risk of in-hospital death in the early studies emerging from China (Zhou F, et al. 2020). The true prevalence of COVID-19-associated thrombosis is unknown, as the majority of studies to date have lacked systematic and comprehensive investigation protocols. As a result, individuals infected with COVID-19 faced a risk of venous thromboembolism (VTE) of up to 25%. (Bikdeli B, et al. 2020; Chen G, et al 2020).

At day 17 of symptoms, 23.7 % of patients in the control group developed thrombosis, compared to 11% in the melatonin group (P < 0.05). The aforementioned data are consistent with this study, which established a significant effect of melatonin use on thrombosis.

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Effect of Melatonin on Sepsis in COVID-19 Patients:

Sepsis is defined as organ dysfunction that is potentially fatal as a result of an abnormal host response to infection (Singer M, et al. 2016). Sepsis may be caused by a number of different pathogens. Sepsis is primarily caused by bacterial infection. However, up to 42% of sepsis patients had negative cultures, implying a nonbacterial cause (Phua J, et . 2013). Although almost any virus can cause sepsis in susceptible patients, viral sepsis is a very rare clinical diagnosis. Increased awareness, early detection of viral sepsis, rapid administration of appropriate antiviral medications, and prompt treatment can significantly reduce viral sepsis-related deaths (Reinhart Konrad, et al. 2017). With time, a significant difference in the development of sepsis was observed between the melatonin and control groups (at day 17 of symptoms, 35.5 percent of patients in the control group develop sepsis versus 8.5 percent in the melatonin group) (P < 0.001). Although no study has been conducted on the effects of melatonin on sepsis in COVID-19 patients, a recent clinical trial found that intravenous administration of 60 mg/d of a melatonin formulation improved septic patients, decreased their mortality to zero, and decreased their hospital stay by 40%. (Dario A. et al. 2020). Another trial used 9 mg of melatonin per day in COVID-19 patients showed significant reduction of hospital stay duration (p < 0.05) and improved clinical symptoms as well as the level of CRP and the pulmonary involvement in the melatonin group (P < 0.05) (Gholamreza, et al. 2020). This trial tested the effect of melatonin tablet 10 mg as it is the available dosage form in our country and to assure good compliance.

Effect of Melatonin on Mortality rate in COVID 19 Patients:

As previously demonstrated, thrombosis and sepsis associated with higher mortality rate & were improve by melatonin administration. As a result, it is entirely reasonable that melatonin resulted in a lower mortality rate in COVID-19 patients. This implied effect of melatonin was quantified directly in this study, which found that 17.1% of in-hospital patients in the control group died compared to 1.2 percent of patients in the melatonin group (P< 0.001).

The limitations of this trial were the open labeled and single-centered which could restrict the generalizability of the results.

Conclusion

The results of this study demonstrated that oral melatonin, when added to standard of care, was more effective than standard of care alone in patients hospitalized with severe COVID-19. Improved thrombosis, sepsis, and mortality rates support the adjuvant melatonin's efficacy in mitigating this infectious disease. Given melatonin's superior performance as a cheap, highly safe, and readily available medication, it is strongly recommended to be addressed in future studies.

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