Perioperative melatonin in COVID-19 patients:benefits beyond sedation and analgesia

Abhijit S.Nair

Department of Anaesthesiology,Ibra Hospital,Ministry of Health-Oman,Ibra,Sultanate of Oman

Abstract Cytokine storm in coronavirus disease 2019 (COVID-19) patients leads to acute lung injury,acute respiratory distress syndrome,multiorgan dysfunction,shock,and thrombosis thus contributing to signif icant morbidity and mortality.Several agents like steroids,ascorbic acid,vitamins (C,D,E),glutathione,N-acetylcysteine have been used and several studies are underway to identify its effi cacy in addressing undesirable eff ects due to COVID-19 illness.Among several experimental modalities based on expert opinion and anecdotal data,melatonin is one molecule that appears promising.Owing to its anti-inf lammatory,anti-oxidant,and immunomodulatory properties,melatonin can be an important agent used as a component of multimodal analgesia in COVID-19 patients,suspected patients,and patients with exposure to positive patients undergoing emergency or urgent surgeries.Further research is required to know the optimal time of initiation,dose,and duration of melatonin as an adjunct.

Key words: anesthesia;antioxidants;COVID-19;cytokine;inf lammation;melatonin;multimodal analgesia;perioperative;surgery

THE SPECTRUM OF COVID-19 INFECTION

In severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infections,there are marked inf lammatory and immune responses leading to cytokine storm.This is because of the imbalance between the pro-inf lammatory and anti-inf lammatory mediators in the lung parenchyma.This eventually leads to apoptosis of epithelial cells and endothelial cells;subsequently,vascular leakage,abnormal T cell,and macrophages responses ensue and induce acute lung injury (ALI),acute respiratory distress syndrome (ARDS),multi-organ dysfunction,or even death.1,2The components of a cytokine storm are interferons,interleukins,chemokines,colony-stimulating factors,and tumor necrosis factor-α.3SARS-CoV-2 infection intrudes the host cells via S-spike protein by binding to angiotensinconverting enzyme 2 for internalization which is aided by transmembrane serine protease 2 protease.Once internalized,the viruses attack pulmonary parenchyma,myocytes,and endothelial cells of vasculature which leads to a cascade of inf lammatory changes like tissue edema,degeneration,and necrosis.Proinf lammatory cytokines like interleukin-6,interleukin-10 and tumor necrosis factor α,granulocyte colony-stimulating factor,monocyte chemoattractant protein 1,macrophage inf lammatory protein 1α,and increased expression of programmed cell death 1,T-cell immunoglobulin,and mucin domain 3 are responsible for the insult.The systemic inf lammation owing to this leads to ARDS,lowering of immunity,myocardial cell damage,and gastrointestinal system insults like diarrhea,vomiting,and abdominal pain.4,5Several modalities have been used by clinicians to address the cytokine storm to reduce the damage caused by them.The most commonly used modalities are corticosteroids,immunoglobulins,interleukin antagonists,interferon-α,blood purif ication therapy like convalescent plasma.6One such drug under investigation with a lot of promise appears to be melatonin (Figure 1).We searched PubMed,Google Scholar database,and clinicaltrials.gov using keywords:COVID-19;cytokine;melatonin;anesthesia;inf lammation;antioxidants;surgery to investigate proven effi cacy of melatonin in the perioperative period as an antioxidant,immunomodulator,adjunct to multimodal analgesia,and anti-COVID-19 properties.

Figure 1:Various benef icial properties of melatonin when used in COVlD-19 patients.

CD147 AND ITS IMPLICATION IN COVID-19

CD147 is a type I transmembrane protein that is implicated with unfavorable outcomes during viral infections including SARS-CoV-2.This is mediated through pro-inf lammatory cytokines like interleukin-6,interferon-λ,tumor necrosis factor-α,and monocyte chemo-attractant protein-1.CD147 has also been found responsible for conditions like multiple sclerosis,myocardial infarction,and cancer proliferation.7,8In SARS-CoV-2 infections,CD147,along with angiotensinconverting enzyme,has been implicated in activation of inf lammation.COVID-19 infection has an initial pulmonary phase in which there is viral replication and inf lammation.The inf lammasome is an important element in the cytokine storm and that reactive oxygen species (ROS) is a potent ligand and direct mediator for triggering NOD-like receptors P3 inf lammasome.9With the activation of ROS and inf lammasome along with inf lammatory cytokines,there are systemic inf lammatory eff ects like thrombosis,lung injury,and myocardial injury.10Mitochondria of the cell are the main target of ROS produced due to inf lammation.The balance between oxidase and antioxidase determines the generation and elimination of ROS.Increased production of free radical,enhanced activity of mitochondrial inducible nitric oxide synthase,enhanced nitric oxide production,decreased respiratory complex activity,malfunctioning of the electron transport system,and opening of mitochondrial permeability transition pores lead to impaired mitochondrial function.11

MELATONIN - CLINICAL PHARMACOLOGY

Melatonin (5 methoxy-N acetyltryptamine) is a hormone secreted by the pineal gland.Supplemental melatonin has been used by clinicians to manage sleep disorders,delirium,and as an anti-inf lammatory agent in diseases like atherosclerosis,respiratory diseases,and viral infections.The anti-oxidative eff ect of melatonin along with its anti-inf lammatory actions like up-regulating anti-oxidative enzymes (e.g.,superoxide dismutase),down-regulating pro-oxidative enzymes (e.g.,nitric oxide synthase) is well known.12-15Melatonin also interacts directly with free radicals,functioning as a free radical scavenger.Another favorable eff ect of melatonin is its immunomodulatory eff ects.16This is supposed to be due to its anti-inf lammatory eff ects in certain conditions and also antioxidative eff ects.

Melatonin exerts anti-inf lammatory eff ects through various pathways.Sirtuin-1 mediates anti-inf lammatory actions of melatonin by inhibiting high mobility group boxechromosomal protein 1,and down-regulating the polarization of macrophages towards the pro-inf lammatory type.17Nuclear factor kappa-B (NF-κB) has pro-inf lammatory and pro-oxidative activities in ALI.The anti-inf lammatory eff ect of melatonin suppresses NF-κB activation by down-regulating NF-κB activation in T cells and lung tissue.Experimental research suggests close interaction of sirtuin-1,NF-κB,and nuclear factor erythroid 2-related factor 2 suggests their participation in the coronavirus-induced ALI/ARDS.18Melatonin directly scavenges oxygen free radicals,upregulates the expression of antioxidase,and downregulates the expression of oxidase.Therefore,melatonin is also referred to as a mitochondriatargeted antioxidant.19

Melatonin does not have any antiviral eff ects.However,the anti-inf lammatory and anti-oxidant properties of melatonin have been found benef icial in a series of patients with viral lung infections.In a dose ranging from 3 to 10 mg per day,oral melatonin has been found safe in critically ill patients.20Melatonin def iciency in older adult patients is considered as a factor responsible for adverse outcomes as the def iciency leads to immunosuppression.

MELATONIN AS ADJUVANT IN COVID-19 TREATMENT

Reducing inf lammation and enhancing immunity is important in COVID-19 patients to prevent mortality and morbidity.The use of antiviral drugs in early stages when viral replication and infectivity is high appears to be benef icial.Once that stage is crossed,i.e.,from the second-week cytokine storm sets in which is responsible for ALI/ARDS,multiorgan dysfunction,and other adverse events like thrombosis.

The safety of melatonin as an adjunct to multimodal analgesia is well established.Melatonin has antinociceptive properties and has been shown effi cacious in managing acute postoperative pain and chronic neuropathic pain as a component of multimodal analgesia.21-23Due to its anti-inf lammatory,antioxidant,and antinociceptive eff ects,anesthesiologists can consider starting oral melatonin to COVID-19 positive patients who are coming for emergency or urgent surgeries.When administered orally,the Tmax of oral melatonin is about 50 minutes in healthy volunteers.Ramlall et al.24retrospectively reviewed data from 791 intubated patients with COVID-19.Authors concluded that patients who were treated with melatonin after intubation had a statistically signif icant positive outcome (demographics and comorbidities adjusted hazard ratio:0.131,95% conf idence interval:0.076 to 0.223).However,the authors did not mention the dose and duration of melatonin therapy in these patients.There are several ongoing studies which are currently ongoing which is investigating the dose,effi cacy,safety,and duration of melatonin use in critically ill COVID-19 patients.25-27A study has suggested a dose ranging from 5-8 mg/kg per day in COVID-19 patients for its anti-inf lammatory and immunomodulatory eff ects.28In critically ill patients,bioavailability will be aff ected by gut malabsorption and factors aff ecting the f irst-pass metabolism.Based on a systematic review done by Harps?e et al.29the authors concluded that the bioavailability of oral melatonin is 15%.Results of ongoing studies could guide clinicians regarding the safest possible dose and acceptable duration of melatonin use in critically ill COVID-19 patients.Lower segment caesarean sections posed a unique challenge during the COVID-19 pandemic both while dealing with positive patients and also while dealing with reverse transcriptase polymerase chain reaction negative or suspected patients.Reports which are available from several centers have mentioned that there was an increased rate of caesarean section during the pandemic.30The safety and effi cacy of preoperative melatonin was explored earlier by Khezri et al.31in patients undergoing caesarean section and it was found that the time to rescue analgesia was prolonged though not signif icant statistically.In this pandemic,researchers can utilize the opportunity to determine the optimal dose of melatonin as premedication before caesarean section and also the anti-inf lammatory,anti-oxidant properties of melatonin in COVID-19 parturients undergoing surgery.

CONCLUSION

Melatonin is a safe drug that could be used in therapeutic doses at any stage when reverse transcriptase polymerase chain reaction is positive for COVID-19 as there are no recommendations right now for the optimal time of starting melatonin.Anesthesiologists could consider using melatonin as a part of multimodal analgesia when dealing with COVID-19 patients,suspected patients,or patients who have history of exposure as it could provide additional benef it.Further,ongoing studies could reveal the optimal time of starting,safest possible dose,and duration of melatonin therapy to provide anti-inf lammatory and anti-oxidative benef its in COVID-19 patients.

Author contributions

Conception of the idea,research design,manuscript writing and editing,review of the literature are all by the author.

Conflicts of interest

None.

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Nil.

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Peer review

Externally peer reviewed.

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