Melatonin Pharmacological Blood Levels Increase Total Antioxidant Capacity in Critically Ill Patients

Abstract

In this study, the aim was to test the biochemical effects of melatonin supplementation in Intensive Care Unit (ICU) patients, since their blood levels are decreased. Sixty-four patients were enrolled in the study. From the evening of the 3rd ICU day, patients were randomized to receive oral melatonin (3 mg, group M) or placebo (group P) twice daily, at 20:00 and 24:00, until discharged. Blood was taken (at 00:00 and 14:00), on the 3rd ICU day to assess basal nocturnal melatonin values, and then during the treatment period on the 4th and 8th ICU days. Melatonin, total antioxidant capacity, and oxidative stress were evaluated in serum. Melatonin circadian rhythm before treatment was similar in the two groups, with a partial preservation of the cycle. Four hours from the 1st administration (4th ICU day, 00:00), melatonin levels increased to 2514 (982.3; 7148) pg·mL^-1 in group M vs. 20.3 (14.7; 62.3) pg·mL^-1 in group P (p < 0.001). After five treatment days (8th ICU day), melatonin absorption showed a repetitive trend in group M, while in group P nocturnal secretion (00:00) was impaired: 20 (11.5; 34.5) pg·mL^-1 vs. 33.8 (25.0; 62.2) on the 3rd day (p = 0.029). Immediately from the beginning of treatment, the total antioxidant capacity was significantly higher in melatonin treated subjects at 00:00; a significant correlation was found between total antioxidant capacity and blood melatonin values (ρ = 0.328; p < 0.001). The proposed enteral administration protocol was adequate, even in the early phase, to enhance melatonin blood levels and to protect the patients from oxidative stress. The antioxidant effect of melatonin could play a meaningful role in the care and well-being of these patients.

Keywords: antioxidants; critical illness; dietary supplements; melatonin; oxidative stress.

Figure 1

Endogenous melatonin secretion in the 3rd day of ICU measured at midnight and 14:00 h, in patients assigned to the two treatments groups before placebo or melatonin tablet administration. The median (25; 75 percentiles) values were 33.8 (25; 62) vs. 32.0 (21; 57) pg/mL at midnight and 16.8 (13; 23) vs. 21.0 (13; 32) pg/mL at 14:00 h, for the two treatment groups, respectively, without significant differences.

Figure 2

Endogenous melatonin secretion in the 3rd and 8th day of ICU measured at midnight (24) and at 14.00 h (14), in patients treated with placebo. The median (25; 75 percentiles) values were 33.8 (25; 62) vs. 20.0 (12; 35) pg/mL at midnight and 16.8 (13; 23) vs. 10.9 (7; 22) pg/mL at 14:00 h, at the 3rd and 8th day, respectively.

Figure 3

Serum melatonin and total antioxidant capacity (TAC) values measured in critically-ill patients at midnight (N) and at 14:00 h (D) of the 3rd, 4th, and 8th ICU day. Patients were randomized to receive either melatonin 3 mg at 20:00 h and midnight or placebo from the 4th ICU day. Data are represented as “box and whiskers” plots: within each plot, the box is bordered at the first (Q1) and third (Q3) quartile of the variable, and is cut by a line corresponding to the median; whiskers extend from the box to the 95% confidence interval. Dots represent outlier values. Comparisons were made by Wilcoxon rank-sum test for unmatched data. * denotes p < 0.05 between groups.

Figure 4

Correlation between serum melatonin and serum total antioxidant capacity (TAC) measured in all available samples, taken from critically-ill patients at midnight and at 14:00 h of the 3rd, 4th, and 8th ICU day; the patients had received melatonin or placebo. Analysis was done by Spearman rank correlation. ρ: Spearman correlation coefficient. Line represents the linear prediction; gray belt is the 95% confidence interval; points are all the available couples of observed values.

Figure 5

May Grünwald-Giemsa-stained lymphocyte of a control subject (a); and a confocal image showing inducible Nitric Oxide Synthase (iNOS) positivity (b); and cytochrome C positivity (c) lymphocytes of a placebo treated critically-ill patient. Scale bar = 20μm.

Figure 6

Timeline of the study. The patients were admitted to the ICU on day 1, and enrolled in the study during day 2. During the 3rd ICU night and day (midnight and 14:00 h), blood samplings were done to measure the baseline blood melatonin and total antioxidant capacity. At 20:00 of the 3rd ICU day, treatment with melatonin or placebo was begun: each patient received a 3 mg tablet of melatonin at 20:00 h and midnight (total 6 mg daily), until ICU discharge. Post-treatment blood samples were collected both in the early (4th night and day) and in the late (8th night and day) periods.