Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis*

Abstract

OBJECTIVE: Melatonin is involved in the regulation of the sleep-wake cycle and exhibits multiple interactions with the neuroendocrine and the immune system. Melatonin secretion in healthy individuals follows a stable circadian rhythm. Critical illness, continuous administration of drugs, and loss of external zeitgeber might impair the circadian rhythm of melatonin secretion in the intensive care unit (ICU), thereby compromising the physiologic stress-induced immune response. DESIGN: Prospective, controlled clinical study. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Seventeen septic, sedated ICU patients (group A); 7 nonseptic ICU patients (group B); and 21 control patients (group C) were studied. MEASUREMENTS AND MAIN RESULTS: 6-Sulfatoxymelatonin (aMT6s) was determined from urine samples taken at 4-hr intervals over a total period of 24 hrs. aMT6s was measured by enzyme-linked immunosorbent assay. Circadian mesors, phase amplitudes, and timing of the acrophase were assessed by cosinor analysis. Differences between groups were calculated by contingency data analysis and by analysis of variance. Circadian mesors of urinary aMT6s were 3904 +/- 1597, 2622 +/- 927, and 3183 +/- 1514 ng/4 hrs in groups A, B, and C, respectively (p = NS). aMT6s exhibited significant circadian periodicity in only 1/17 (6%) patients of group A but in 6/7 (86%) patients of group B and in 18/23 (78%) patients of group C (group A vs. groups B and C: p = .0001) Phase amplitudes were markedly lower in group A (1071 +/- 1005 ng/4 hrs) compared with group B (2284 +/- 581 ng/4 hrs, p = .009) and C (2838 +/- 2255 ng/4 hrs, p = .006). The acrophase was significantly delayed in patients of group A (10:35 am +/- 255 mins) compared with group B (05:43 am +/- 114 mins, p = .01) and group C (4:20 am +/- 107 mins, p < .0001). In sepsis survivors, aMT6s excretion profiles tended to normalize, but still lacked a significant circadian rhythm at ICU discharge. CONCLUSION: The present study revealed striking abnormalities in urinary aMT6s excretion in septic ICU patients. In contrast, circadian rhythm was preserved in nonseptic ICU patients, indicating that impaired circadian melatonin secretion in septic patients is mainly related to the presence of severe sepsis and/or concomitant medication. Further investigations are required to examine the underlying pathophysiologic mechanism and the clinical implications of this finding.