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A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in surgical patients with severe sepsis admitted to the intensive care unit

December 2022

Mansilla-Roselló A, Hernández-Magdalena J, Domínguez-Bastante M, et al. A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in surgical patients with severe sepsis admitted to the intensive care unit [published online ahead of print, 2022 Nov 25]. J Pineal Res. 2022;e12845. doi:10.1111/jpi.12845


A small (N=29) unicenter, phase II double-blind, randomized, placebo-controlled trial was conducted to analyze the effects of intravenous melatonin on patients with severe sepsis that requires surgery.  The dose of 60 mg of melatonin was given to 15 individuals intravenously for 30 minutes per day for 5 days. In the melatonin-treated group, there was a decrease in redox status, neutrophil to lymphocyte ratio, mortality rates, and hospital stays reduced by almost 20%. 

Our comments/takeaway from the article

High-dose IV melatonin administration improved clinical outcomes of ICU patients with sepsis that required surgery. While further studies are needed for the delivery and dose of melatonin for this purpose, the antioxidant and anti-inflammatory properties of melatonin appear to show promise as a possible adjuvant therapy for those with sepsis. Though melatonin is not being suggested as a standalone therapy for sepsis, we would stress the importance of utilizing all needed medical therapies to manage sepsis and all other infections. Our key takeaway from this article is that this study provides additional insight into the variation of dosing and delivery forms of melatonin that can be utilized clinically. 

Article summary

The World Health Organization (WHO) has emphasized the importance of developing therapies to treat sepsis.  At present, specific options are not available to address the cytokine storm, organ failure, and higher mortality rates in this population. The authors hypothesized that melatonin would be beneficial for clinical outcomes in patients with sepsis due to the antioxidant and anti-inflammatory properties of melatonin and that the delivery intravenously would be favorable due to low intestinal absorption process in sepsis. 

In this unicenter, phase II double-blind, randomized, placebo-controlled trial, the treatment group received a continuous IV of 60 mg melatonin, dissolved in 500 mL 5% dextrose serum that was administered for 30 minutes daily for 5 days, while also receiving appropriate medical and surgical care. Patients were followed for 40 days after surgery or until death. 

Inclusion criteria:

  • Patients with severe sepsis (as defined by the American College of Chest Physicians/Society of Critical Care Medicine criteria), that required surgical intervention. 

Exclusion criteria:

  • <18 years old

  • Pregnant

  • Medical or surgical terminal illness

  • Impaired mental abilities

  • Psychiatric illness under treatment

  • Melatonin hypersensitivity

  • Melatonin use 2 days prior to surgery 

The primary outcome was any incidence of organ dysfunction, determined by Sequential Organ Failure Assessment (SOFA). The secondary outcomes included all-cause mortality, oxidative stress status, and inflammatory responses. 

Results included the following:

  • SOFA scores decreased significantly in both groups at the end of the trial (Day 5), though the melatonin group had a greater reduction, suggesting the overall condition of these patients was improved.

  • A 19.60% reduction in hospital stays: 21.42 days for the melatonin-treated group compared to 26.64 days for the placebo group.

  • Reduced mortality rates in the melatonin group (20%) compared to 35.7% in the placebo group.

  • Significant changes in oxidative stress status, as assessed by the reduction of activity and expression of the antioxidant enzymes superoxide dismutase ( SOD), catalase (CAT), glutathione peroxidase (GPx), and reductase (GRd), which were no longer activated or required in the presence of melatonin, as melatonin scavenges superoxidases and peroxidases.

  • Significant increases (p<0.05) in blood pH values in the melatonin group, suggesting improvement in the physiological condition of the individuals.

  • Malondialdehyde (MDA), an index of lipid peroxidation, was significantly higher at the start of the trial for the melatonin group, however, upon administration of melatonin, this value decreased within 24 hours, with a transient increase at day 4, followed by a subsequent decrease on day 5.

  • The neutrophil-to-lymphocyte ratio (NLR) significantly decreased (P<0.05) in the melatonin group. These are markers of inflammation and higher ratios have been directly related to an unfavorable prognosis and mortality rates.

  • Procalcitonin levels (a measure of infection and inflammation) were higher at the start of the trial in the melatonin group compared to the placebo group, however, there was a more pronounced and significant (p<0.05) decrease by day 5 in the treated group. Levels for both groups were still considered elevated. 

The authors noted a previous study that was completed using oral melatonin in septic patients, in which no significant changes were observed.  They state, “Our clinical trials, which was carried out on septic ICU patients, suggests that IV melatonin administration may be better than the oral method.”  While additional studies are needed, this study suggests that high-dose, IV melatonin may be a possible therapy for sepsis. 

No side effects were noted during this trial, further suggesting the safety of melatonin. 

Author’s limitations include:

  • Short duration of therapy (5 days)

  • Short duration of administration of melatonin (1 time per day), knowing melatonin has a short half life.

  • First clinical trial of its kind, resulting in limited permission of the number of patients studied, length of time studied, and dose utilized. 

Other limitations noted in our review:

  • Unknown medications used during the trial period

  • Unknown history of medical conditions

  • Additional inflammatory markers were not evaluated (i.e., hs-CRP) to further assess the anti-inflammatory influence melatonin may have. 

Article review completed by Kim Ross, DCN

Content reviewed by Deanna Minich, PhD

December 19, 2022

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