Abstract
BackgroundAbolished 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.MethodsAll 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.ResultsMelatonin 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).ConclusionMelatonin 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.
Highlights
Sleeplessness and sleep fragmentation/disruption often lead to delirium, and are associated with increased mortality and are a frequent complication in the critically ill patient [1,2,3,4]
Secondary outcomes The risk of developing delirium or coma (NMI) during the study period was significantly lower in the nonsedated group compared to the sedated, based on CAM-Intensive care unit (ICU) scores performed twice per day (14.00 and 22.00, Fig. 4)
Patients were considered delirious at the time if they had an Richmond agitation scale score (RASS) score lower than – 3 or if they tested positive on the CAM-ICU test conducted as closely to 14.00 and 22.00 as could be achieved (Fig. 4)
Summary
Sleeplessness and sleep fragmentation/disruption often lead to delirium, and are associated with increased mortality and are a frequent complication in the critically ill patient [1,2,3,4]. The underlying causes are Oxlund et al Ann. Intensive Care (2021) 11:40 multifactorial, but comorbidities, primary illness, pain, medical treatment/sedation, alarms, lighting, sepsis, and mechanical ventilation are important factors [1, 6, 7]. Melatonin plays multiple physiological roles in the regulation of the sleep/wake cycle and bodily circadian entrainment by acting as an internal 24-h biological clock [6]. 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. Melatonin plays a crucial role as part of the circadian and sleep/wake cycle. 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
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