Serum melatonin concentration in critically ill patients randomized to sedation or non-sedation

Jakob Oxlund, Torben Knudsen, Thomas Strøm, Jørgen T Lauridsen, Poul J Jennum, Palle Toft, Jakob Oxlund, Torben Knudsen, Thomas Strøm, Jørgen T Lauridsen, Poul J Jennum, Palle Toft

Abstract

Background: Abolished circadian rhythm is associated with altered cognitive function, delirium, and as a result increased mortality in critically ill patients, especially in those who are mechanically ventilated. The causes are multifactorial, of which changes in circadian rhythmicity may play a role. Melatonin plays a crucial role as part of the circadian and sleep/wake cycle. Whether sedation effects circadian regulation is unknown. Hence, the objective of this study was to evaluate the melatonin concentration in critically ill patients randomized to sedation or non-sedation and to investigate the correlation with delirium.

Methods: All patients were included and randomized at the intensive care unit at the hospital of southwest Jutland, Denmark. Seventy-nine patients completed the study (41 sedated and 38 non-sedated). S-melatonin was measured 3 times per day, (03.00, 14.00, and 22.00), for 4 consecutive days in total, starting on the second day upon randomization/intubation. The study was conducted as a sub-study to the NON-SEDA study in which one hundred consecutive patients were randomized to sedation or non-sedation with a daily wake-up call (50 in each arm).

Primary outcome: melatonin concentration in sedated vs. non-sedated patients (analyzed using linear regression). Secondary outcome: risk of developing delirium or non-medically induced (NMI) coma in sedated vs. non-sedated patients, assessed by CAM-ICU (Confusion Assessment Method for the Intensive Care Unit) analyzed using logistic regression.

Results: Melatonin concentration was suppressed in sedated patients compared to the non-sedated. All patients experienced an elevated peak melatonin level early on in the course of their critical illness (p = 0.01). The risk of delirium or coma (NMI) was significantly lower in the non-sedated group (OR 0.42 CI 0.27; 0.66 p < 0.0001). No significant relationship between delirium development and suppressed melatonin concentration was established in this study (OR 1.004 p = 0.29 95% CI 0.997; 1.010).

Conclusion: Melatonin concentration was suppressed in sedated, critically ill patients, when compared to non-sedated controls and the frequency of delirium was elevated in sedated patients. Trail registration Clinicaltrials.gov (NCT01967680) on October 23, 2013.

Keywords: Circadian; Delirium; Melatonin; Non-sedation; Rhythm; Sedation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Consort
Fig. 2
Fig. 2
Mean melatonin concentration throughout the 4-day study period including 95% confidence interval. X axis; day and time of the sample (e.g., 2–14 = day 2 time 14:00). The reference curve is hypothetical and based on the literature, mainly M. Karasek et al. and demonstrates mean concentration of melatonin diurnal variation among healthy individuals in the age group of the study population [5, 12, 19]
Fig. 3
Fig. 3
Mean RASS score throughout the 4-day study period including 95% confidence interval
Fig. 4
Fig. 4
Patients N with positive and negative CAM-ICU test evaluated twice per day. UTE; Unable To Evaluate

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