Delirium is a complex neuropsychiatric syndrome characterized by cognitive impairment and attentional deficits. Delirium in the intensive care unit (ICU) is of high incidence (30%–60%),[2–4] and strongly associated with adverse outcomes, such as increased mortality, prolonged length of stay in intensive care units (ICU-LOS), increased costs, and long-term cognitive sequelae. As increasingly recognized, delirium has turned into one of the most concerned problems for intensive care physicians. Despite delirium in the critically ill appears to be of high incidence and associated with adverse outcome, clinical strategies have been very limited.
Melatonin is a neuro-hormone exerting multiple biological effects, mainly in regulating diurnal rhythms, and also in modulating inflammatory as well as immune responses.[7,8] Abundant evidence has indicated that decreasing melatonin levels were linked with delirium. Melatonergics includes melatonin and other melatonin agonists such as ramelteon. Whether supplementation of exogenous melatonin and melatonin agonists could reduce the risk of delirium remains uncertainty. Several randomized controlled studies (RCTs) have been conducted related to the issue. Taking Sultan et al study as an example, 3 hundred elderly patients undergoing hip arthroplasty were randomly assigned to one of four groups; these groups were administrated with melatonin, or midazolam, or clonidine, or no medication, respectively. The results of this study showed that melatonin was associated with significant reduction in incidence of delirium compared with control group as well as the other 2 parallel groups. However, a meta-analysis including four RCTs indicated no significant difference. Since then, several well designed RCTs have been conducted.[12–15] A recent meta-analysis evaluated delirium as a subset but only included three RCTs for this result. With the updated results,[12–15] we aimed to conduct a meta-analysis subjected with the critically ill, in attention to re-evaluating the efficacy of melatonergics in prevention of delirium in ICU.
2 Review question
Could melatonergics reduce incidence of delirium in critically ill patients?
3.1 Study registration
The study has been registered on the PROSPERO (registration number: CRD42019138863) based on the PRISMA-P guidelines.
3.2 Search methods
Three electric databases (PubMed, Cochrane Library, and Embase) will be searched without language restriction to identify RCTs published from 1960 to April 2019. The reference lists will be searched manually for potentially relevant articles. A search strategy has been developed for the 3 databases as a combination of “melatonin”, “melatonergic”, or “ramelteon” in all fields, and “critically ill”, “critical illness”, “critical care”, or “intensive care” in all fields. The outcome keyword of delirium will not be included in the preliminary screening to avoid missing of potentially relevant references.
3.3 Inclusion criteria
We include studies designed as RCT.
The study subjects consist of critically ill adults (age ≥18 18 years).
Melatonergics including melatonin and melatonin agonists are administrated as interventions. The control groups could be no intervention, placebo, or other medication.
The primary outcome measure is incidence of delirium. The secondary outcome is length of stay in ICU (ICU-LOS).
3.4 Exclusion criteria
We exclude studies not relevant to ICU. Studies of suboptimal quality (Modified Jadad Score 0-4) will also be excluded.
3.5 Data collection and analysis
3.5.1 Study screening
The 2 reviewers (ZYB and JZM) will screen the search results according to the title and abstract independently. After the full text obtained, the 2 reviewer will screen the references for potentially relevant studies. The flow chart of selection process will be summarized and reported.
3.5.2 Data extraction
The 2 reviewers (ZYB and JZM) will independently extract data to fulfill a predesigned form including the characteristics of the studies, journal, year of publication, demography and baseline of subjects, intervention and outcomes.
3.5.3 Assessment of study quality
The Cochrane Collaboration's tool will be used to assess selection bias, performance bias, attrition bias and reporting bias. Two reviewers (ZYB and JZM) will independently rate the quality of the RCTs and fulfill the items of risk of bias as low, high, or unclear. Any discrepancies between the 2 reviewers will be solved by a consulting group including two experts (WY and XXM). The quality of evidence resulting from this systematic review was evaluated using the GRADE (Grades of Recommendation Assessment, Development and Evaluation) methodology.[20,21]
3.5.4 Statistical analyses and data synthesis
Review Manager, Version 5.3 will be used for data synthesis. The pooled effects of dichotomous outcomes will be analyzed as risk ratio (RR) using Mantel-Haenszel (M-H) technique and 95% confidence intervals (CIs). The pooled effects of continuous outcomes will be analyzed using weighted mean difference (WMD) and 95% CI. A P value of less than .05 will be considered to be statistically significant.
3.5.5 Assessment of heterogeneity
I2 statistic will be used to estimate statistical heterogeneity (I2 < 30% as low heterogeneity, I2 of 30% to 70% as medium heterogeneity, I2 > 70% as high heterogeneity). Clinical heterogeneity will be assessed by the 2 reviewers (ZYB and JZM) and the consulting group (WY and XXM). If high clinical or statistical heterogeneity is observed, a random effect model will be used. Otherwise, a fixed effect model will be chosen.
3.5.6 Subgroup and sensitivity analyses
Subgroup and sensitivity analyses will be conducted to test the robustness of the primary outcome and to further explore the potential influence factors. Subgroups include
- (1) differed melatonergics including metalonin and remelteon;
- (2) differed age groups including elderly subjects (mean age >60), middle age subjects (mean age 40–60), and younger subjects (mean age <40); and
- (3) differed ICU type including surgical ICU, medical ICU, and mixed ICU. Sensitivity analyses will be conducted by excluding any single RCT.
3.5.7 Assessment of publication bias
A funnel plot will be used to assess publication bias when ten or more RCTs are available for quantitative analysis. Egger test will be performed if included studies are less than ten.
3.5.8 Trial sequential analysis
Assessment of the risk of random errors will be done by trial sequential analysis (TSA) (www.ctu.dk/tsa). The results of TSA will determine whether the evidence in our meta-analysis is reliable and conclusive by providing the boundaries of sample size.
There have been RCTs[10,12,24,25] suggesting that administration of melatonin and melatonin agonist might be a promising medication in prevention of delirium in at-risk population with the following reasons. First, sleep deprivation is a crucial risk factor of delirium. Exogenous melatonergics have been proved to be apparently associated with improvement of sleep quality and prolongation of sleep duration. Meanwhile, reduction of melatonin levels is associated with development of delirium. Thus, supplementation of exogenous melatonin can remedy disordered melatonin levels. Second, delirium is considered to be caused by inflammation of the central nervous system (CNS). Melatonin is an anti-inflammatory drug and antioxidant functions protectively during the inflammatory response. Third, delirium occurs commonly as a side effect of benzodiazepines, the most commonly used sedatives in ICU. Administration of melatonergics to hypnosis could reduce the dosage of benzodiazepines accordingly. However, the previous meta-analysis showed negative results. With the updated RCTs, the results of this meta-analysis will provide advanced evidence on the efficacy of melatonergics in prevention of delirium in critically ill patients.
Conceptualization: Yibing Zhu, Wei Li.
Data curation: Yibing Zhu, Zhiming Jiang.
Software: Huibin Huang, Linlin Zhang, Chao Ren.
Methodology: Yang Wang, Xiuming Xi, Bin Du.
Project administration: Yibing Zhu.
Supervision: Wei Li, Xiuming Xi.
Writing – original draft: Yibing Zhu.
Writing – review & editing: Xiuming Xi, Yongming Yao, Bin Du.
. Olivo SA, Macedo LG, Gadotti IC, et al. Scales to assess the quality of randomized controlled trials: a systematic review
. Phys Ther 2008;88:156–75.
. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101.
. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review
and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.
. Salluh JI, Wang H, Schneider EB, et al. Outcome of delirium in critically ill patients: Systematic review
and meta-analysis. BMJ 2015;350:h2538.
. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306.
. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186–95.
. Di WL, Kadva A, Johnston A, et al. Variable bioavailability of oral melatonin. N Engl J Med 1997;336:1028–9.
. Oldham MA, Lee HB, Desan PH. Circadian rhythm disruption in the critically ill: an opportunity for improving outcomes. Crit Care Med 2016;44:207–17.
. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth 2010;4:169–73.
. Chen S, Shi L, Liang F, et al. Exogenous melatonin for delirium prevention: a meta-analysis of randomized controlled trials. Mol Neurobiol 2016;53:4046–53.
. Vijayakumar HN, Ramya K, Duggappa DR, et al. Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: a double-blind randomised placebo controlled trial. Indian J Anaesth 2016;60:814–20.
. Dianatkhah M, Ghaeli P, Hajhossein Talasaz A, et al. Evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder. J Tehran Heart Cent 2015;10:122–8.
. Abbasi S, Farsaei S, Ghasemi D, et al. Potential role of exogenous melatonin supplement in delirium prevention in critically Ill Patients: a double-blind randomized pilot study. Iran J Pharm Res 2018;17:1571–80.
. Nishikimi M, Numaguchi A, Takahashi K, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit Care Med 2018;46:1099–105.
. Zhang Q, Gao F, Zhang S, et al. Prophylactic use of exogenous melatonin and melatonin receptor agonists to improve sleep and delirium in the intensive care units: a systematic review
and meta-analysis of randomized controlled trials. Sleep Breath 2019;23:1059–70.
. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs. midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–99.
. Oh ES, Fong TG, Hshieh TT, et al. Delirium in older persons: advances in diagnosis and treatment. JAMA 2017;318:1161–74.
. Klein Klouwenberg PM, Zaal IJ, Spitoni C, et al. The attributable mortality of delirium in critically ill patients: prospective cohort study. BMJ 2014;349:g6652.
. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383–94.
. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6.
. van den Boogaard M, Pickkers P S Slooter##AJ, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012;344:e420.
. Wetterslev J, Thorlund K, Brok J, et al. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 2008;61:64–75.
. Al-Aama T, Brymer C, Gutmanis I, et al. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry 2014;29:550.
. Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry 2014;71:397–403.
. de Jonghe A, van Munster BC, Goslings JC, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ 2014;186:E547–56.
. de Rooij SE, van Munster BC. Melatonin deficiency hypothesis in delirium: a synthesis of current evidence. Rejuvenation Res 2013;16:273–8.
. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 2008;24:789–856.
. Ouimet S, Kavanagh BP, Gottfried SB, et al. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 2007;33:66–73.