Prophylactic melatonin for delirium in critically ill patients: A systematic review and meta-analysis with trial sequential analysis

Abstract

Background: Up to 80% of patients in the intensive care unit (ICU) suffer from delirium. Studies on the preventative use of melatonin in the ICU have produced mixed results. We performed a systematic review and meta-analysis to evaluate whether early administration of melatonin reduces the prevalence of delirium in critically ill patients.Methods: We searched Medline, Embase, and the Cochrane Library for randomized controlled trials comparing melatonin or melatonin agonists to placebo in ICU setting. The population included adult patients in the ICU. The primary outcome was the prevalence of delirium. Secondary outcomes included duration of delirium, delirium-free day, serum melatonin concentration, need for sedation, duration of mechanical ventilation, hospital and ICU length of stay (LOS), all-cause mortality, sleep quality, and adverse events. Trial sequential analysis (TSA) was performed on the primary outcome to prevent the risk of random error and multiplicity phenomenon as a result of repeated significance testing across all the included trials.Results: Twelve trials with a total of 2538 patients were analyzed. When all trials were pooled, the incidence of delirium in ICU patients who received melatonin was significantly lower than in those who received placebo (risk ratio, 0.77; 95% confidence interval: 0.61-0.96; I 2 = 56%). There were no significant differences in secondary outcomes including duration of delirium, duration of mechanical ventilation, ICU LOS, hospital LOS, and mortality. TSA indicated that Z-curve crossed the traditional boundary, but did not cross the monitoring boundary for benefit, which indicated that it is still inconclusive that melatonin affects the incidence of delirium.Conclusions: This meta-analysis found that early administration of melatonin may result in a decreased delirium prevalence in critically ill patients. However, the sensitivity analysis of high-quality studies did not support this finding. In addition, TSA demonstrated that the result may have false-positive error. Therefore, this finding should be interpreted with caution. Further studies are needed to examine the effectiveness of prophylactic melatonin on the prevalence and duration of ICU delirium in the future.

Efficacy of melatonin in decreasing the incidence of delirium in critically ill adults: a randomized controlled trial

“…However, its efficacy in preventing delirium has not yet been well established. In their SRMA of 12 trials involving the use of melatonin/ramelteon, Yan et al ( 7 ) reported a significant decrease in the incidence of delirium in the experimental group. ( 15 ) However, a sensitivity analysis and a trial sequential analysis revealed that this conclusion may be due to a false-positive error.…”

“…Entretanto, sua eficácia na prevenção do delirium ainda não foi bem estabelecida. Em sua revisão sistemática e metanálise com 12 estudos sobre o uso de melatonina ou ramelteona, Yan et al ( 7 ) relataram diminuição significativa na incidência de delirium no grupo experimental. ( 15 ) No entanto, uma análise de sensibilidade e uma análise sequencial de estudos revelaram que essa conclusão pode ser devida a um erro falso-positivo.…”

“…The rationale for the use of melatonin for decreasing sleep disturbances and potentially delirium in the ICU is derived from the finding of low plasma melatonin concentrations and abnormal patterns of secretion of melatonin in critically ill patients. ( 6 ) However, a definite prophylactic/therapeutic effect of melatonin has not yet been established, as is evident by the contrary findings reported in systematic reviews and meta-analyses (SRMAs) published by Yan et al and Aiello et al ( 7 , 8 )…”

“…A justificativa para o uso da melatonina na redução dos distúrbios do sono e, possivelmente, do delirium na UTI deriva da constatação de baixas concentrações plasmáticas de melatonina e de padrões anormais de secreção de melatonina em pacientes graves. ( 6 ) Contudo, ainda não foi estabelecido um efeito profilático e nem terapêutico definitivo da melatonina, como fica evidente pelos achados divergentes relatados em revisões sistemáticas e metanálises publicadas por Yan et al e Aiello et al ( 7 , 8 )…”

Delirium in trauma ICUs: a review of incidence, risk factors, outcomes, and management

“…As those guidelines multiple trials and systematic reviews have demonstrated a preventive effect of dex on delirium in both medical and surgical ICU patients [38,39,40 ▪▪ ,41], and a 2022 Intensive Care Medicine rapid practice guideline suggested use of dex as sedation for ventilated patients in the ICU as long as the benefit of decreased delirium was not outweighed by the adverse effects of bradycardia and hypotension [42]. Melatonin and the melatonin receptor agonist Ramelteon have shown promise, but larger analyses report mixed results and effects only in select populations [38,43,44 ▪ ]. The atypical antipsychotic quetiapine has also recently been supported by a few smaller trials, especially in the ICU population [38,45 ▪▪ ,46].…”