Background
Delirium is characterized by an acute disturbance in attention with an altered level of consciousness or disorganized thinking that is not better explained by a pre-existing neurocognitive or medical condition, substance intoxication or withdrawal, or medication side effect [
1]. Patients who develop delirium in the hospital are at a significantly greater risk of other negative outcomes, including the development of dementia, institutionalization, and one-year mortality [
2‐
4]. One study in post-operative cardiac patients suggested that reduced cognition as a result of post-operative delirium had still not fully recovered, even a year following surgery [
5].
While the incidence of delirium in the hospitalized, general medicine population is estimated to be 11–14%, older adults and post-surgical patients are at much greater risk, with an estimated incidence of 20–29% in geriatric medicine patients and 11–51% in surgical patients. Additionally, approximately 56% of hospitalized patients with a history of dementia will develop delirium [
6].
Melatonin is a natural hormone produced by the pineal gland in the brain, and is known to be involved in sleep-wake cycle regulation. It has been studied for a variety of uses, including but not limited to insomnia [
7‐
9], jet lag [
10‐
12], circadian rhythm disorders in the blind [
13‐
15], shift work [
16‐
18], and more recently delirium prevention [
19,
20]. Recent studies suggest that preoperative cerebrospinal fluid melatonin concentrations may be correlated with delirium risk following hip fracture surgery [
21], and that melatonin secretion rapidly declines with age [
22].
There is a growing interest in the use of melatonin for the prevention of delirium in hospitalized patients. Hatta and colleagues examined the effect of ramelteon, a selective type 1 and type 2 melatonin receptor agonist, in older adults (aged 65 to 89) on incidence of delirium in hospitalized patients on general medicine and intensive care units. Patients were randomized to receive ramelteon 8 mg (
n = 34) or placebo (
n = 33) nightly for 7 days and screened for delirium daily. There was a significantly lower incidence of delirium in the ramelteon group, suggesting that ramelteon may be protective against delirium in hospitalized older patients [
19]. Additionally, a 2011 randomized placebo-controlled trial examining the effect melatonin 0.5 mg (
n = 72) or placebo (
n = 73) nightly for 14 days or until discharge on incidence of delirium in hospitalized patients aged 65 years or older suggested that patients receiving preventative melatonin experienced a lower risk of delirium (12.0% versus 31.0%,
p = 0.014) [
20]. However, these studies did not include surgical patients.
Given that limited pharmacological interventions are available to prevent post-operative delirium at this time [
23,
24], the role of melatonin is worthy of investivation. The purpose of this systematic review and meta-analysis was to assess whether perioperative melatonin administration has an effect on the incidence of delirium in older adults undergoing surgical procedures.
Discussion
Currently, there is a very small body of literature examining the use of melatonin for the prevention of postoperative delirium in older adults. In conjunction with clinician input, the exhaustive literature search was driven by a health sciences librarian who is highly experienced in systematic reviews. While the body of literature is small at this time, the findings of this meta-analysis suggest that perioperative melatonin administration may significantly reduce the incidence of delirium in older adults undergoing surgical procedures – a common, yet detrimental complication of surgery in older adults. The odds ratio was highly sensitive to removal of the one study that did not have results in favor of melatonin reducing risk of delirium, resulting in a reduction of the odds ratio from 0.63 to 0.31, and heterogeneity to zero [
29]. One possible explanation for the negative results in this particular study may be due discrepancy among the two study groups related to prior delirium. Even though statistics were not reported for the baseline characteristics, the group receiving melatonin appeared to have a greater percentage of patients with a history of delirium (23.7% versus 17.2% in the placebo group), which is a well-established risk factor for developing delirium [
6,
36]. Additionally, the authors of the de Jonghe study noted that there was an increased probability of type 2 error, as they had a large number of patients who were excluded post-randomization (withdrawal of consent, delirium at admission, loss to follow-up, etc.). Only 378 patient data were analyzed, while 444 patients were randomized, increasing risk of attrition bias [
29].
While the Kendall’s tau coefficient (p = 0.78) is non-significant, visual inspection of the funnel plot appeared to indicate publication bias in the present meta-analysis. This is likely due to the small number of studies that were eligible for inclusion in the meta-analysis.
There are currently three sets of clinical guidelines that can be applied to the management of delirium in the inpatient setting: The American Geriatrics Society (AGS) Clinical Practical Guideline for Postoperative Delirium in Older Adults; the Society of Critical Care Medicine Clinical Practice Guideline on Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in Intensive Care Unit; and the American Psychiatric Association (APA) Practice Guideline [
37‐
39]. None of the three guidelines made recommendations for pharmacological intervention for the prevention of delirium. The AGS guidelines specifically acknowledge melatonin as being an agent considered for the prevention of delirium, but noted that their practice guidelines did not address it due to lack of evidence [
37]. The PAD guidelines also state that there is a lack of data for an agent that effectively prevents delirium [
38].
This meta-analysis has several limitations. First, the few studies that met inclusion criteria were small, and not all met their predefined statistical power [
29]. By using a fixed effects model for this narrowly defined population, the findings presented are restricted to the population included in the identified studies and are not generalizable at this time. In addition, many well-known predisposing and precipitating risk factors for delirium were not reported in all studies [
40]. For example, time from admission to surgery, body mass index, cognitive impairment, depression, uncontrolled pain, intraoperative blood loss, baseline functional status, and use of medications that could increase delirium risk [
6,
40‐
46] are all possible risk factors for developing delirium. Thus, it is difficult to assess whether intervention and control groups were at similar baseline risk.
Another limitation is the heterogeneity of included studies with regards to type of surgical procedure and melatonin dosing. Because melatonin is not regulated by the United States Food and Drug Administration, dose standardization is not guaranteed unless the manufacturers voluntarily submit their products for strength and purity testing [
47]. Assuming that the doses reported were accurately reflecting the contents of the studied products, one potential explanation for the negative result in the de Jonghe study is that the melatonin dose was lower than the other (3 mg versus 5 mg or more) [
29]. Additionally, while the requirement for an average age of 50 years and older increased the number of studies meeting inclusion criteria, it also led to a wide age variability. Given the small number of studies, it is difficult to ascertain whether older age (e.g.: 85 years and older versus 65 and older) had any effect on benefit, though the study with the oldest average age (84.1 and 83.4 in the intervention and control groups, respectively) was the one study that did not show benefit with melatonin [
29]. While this study suggests that melatonin may have a protective effect against delirium when used in the individuals included in these studies, optimal dosing and ages at which patients are conferred the greatest benefit have yet to be determined.
One of the most prominent sources of variability among included studies was in delirium assessment methods. The Confusion Assessment Method is the current gold standard for delirium assessment, but many studies used alternative tools [
48]. One study included delirium as a secondary outcome, and it is unclear from the methodology report whether this was a pre-determined endpoint and how regularly potential incidence of delirium was assessed.
Melatonin remains an agent of interest due to is its relatively benign side effect profile. A 2005 systematic review and meta-analysis of ten studies involving 222 patients receiving melatonin for the treatment of primary sleep disorders reported 13 headaches, 10 cases of dizziness, 3 cases of nausea, and 3 cases of drowsiness in the cohort of subjects receiving melatonin [
49]. When compared to placebo, the incidence of these events was not statistically significant.
With relatively few side effects and minimal pharmacologic options for the prevention of delirium, melatonin continues to be an agent of interest. While preparing this manuscript, our literature search yielded a 2002 case report of melatonin 2 mg daily used to successfully prevent post-operative delirium in a male patient with a history of delirium undergoing surgery on an infected knee joint [
50]. We also identified one published protocol aiming to assess the efficacy of melatonin 3 mg versus placebo daily for the prevention of postoperative delirium in patients aged 50 and older who are undergoing cardiac surgery [
51]. Another ongoing study aims to examine the potential benefits of melatonin related to delirium in high-risk palliative oncology inpatients; however, this study is not specific to the surgical population [
52]. Future research should re-examine this question when additional, more comprehensive data are available to obtain a more reliable estimate.
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