Article Title/Citation
Study objectives/purpose
(and research hypothesis, if
applicable)
Brief background (why
issue is important, summary
of previous literature)
Prophylactic melatonin for delirium in intensive care (Pro-MEDIC): a randomized controlled trial
- Purpose: To determine if prophylactic administration of melatonin in critically ill patients decreases
the incidence of ICU related delirium.
- Hypothesis: Early administration of melatonin is effective in reducing delirium in critical ill patients
- The prevalence of delirium to associated with poorer outcomes in the ICU including:
o Increased length of stay
o Increased duration of mechanical ventilation
o Need for physical restraints
o Poorer functional status
o Cognitive impairment
o Increased admission to residential care
o Increased medical costs
-
No pharmacological agents have been shown to convincingly decrease the incidence of delirium
Melatonin regulates the sleep-wake cycle, administration improves sleep quality and duration
Serum melatonin concentrations may be lower in patients with delirium in comparison to nondelirious patients in the critical care setting.
Previous studies have reported improved sleep quality and duration in critical ill patients who
received melatonin
Funding sources
-
The Western Australia department of health and the John Hunter Charitable Trust Fund
Study design and
methodology
-
METHODS
Study design: Multicenter, randomized, placebo-controlled, double-blind trial. (n = 850)
Treatment arms: 4 mg melatonin once daily at 2100 or a placebo for up to 14 days in the ICU
Data collection: Twice daily assessments for symptoms of delirium using CAM-ICU scores
Patient selection &
enrollment [inclusion/ exclusion
-
Inclusion criteria:
 ≥18 years or older
 ICU admission with an expected LOS greater than 72 h
 Enrolled within 48 h of ICU admission
-
Exclusion criteria:
 Patients receiving melatonin prior to admit
 Pregnant or breast feeding
 Neurological or hepatic impairment
 No enteral route for administration
-
Primary outcome: percentage of delirium-free episodes
-
Secondary outcomes:
criteria]
Outcome measures/
endpoints







Statistical analyses
-
Severity of delirium
Delirium and Coma-free days
Sleep quality (measured by Richards-Campbell Questionnaire)
ICU and hospital length of stay
Duration of mechanical ventilation
Mortality
ADRs
Differences were considered statistically significant when P values are < 0.05, and 95% confidence
intervals (95% CI)
-
Enrollment & baseline
characteristics
Summary of primary and
secondary outcomes
including subgroup analysis,
etc. Be sure to include both
efficacy and safety
parameters, if appropriate
Author’s conclusions
-
-
Study strengths
-
Study limitations
-
Applicability and impact
on pharmacists/healthcare
providers
Resident Conclusions and
recommendations
RESULTS
Average age of 62
Male (59.1% vs 66.4% control group)
Apache score of 17.3% vs 17.5%
CAM positive baseline 9.6% vs 8.3%
Admission etiology was mostly Emergency at 81.9% vs 80.1%
And their diagnosis type for being in the ICU was respiratory at 27% followed by
cardiovascular at 22%
No significant difference in the average proportion of delirium-free assessments per patient
between the melatonin and placebo groups (79.2 vs 80% respectively, p = 0.547)
No significant difference in any secondary outcomes including ICU LOS (median: 5 vs 5 days, p =
0.135), hospital LOS (median: 14 vs 12 days, p = 0.816), mortality at any time point including at 90
days (15.5 vs 15.6% p = 0.948)
No significant difference in the requirement of anti-psychotics, sedatives or physical restraints, or
in the duration of mechanical ventilation
No serious adverse events reported in either group
AUTHORS’ DISCUSSION & CONCLUSIONS
Short LOS
Dose of melatonin may be too low
Limited ICU setting
Study consistent with critical ill patients having low to non-existent melatonin levels.
Using melatonin early and continued throughout the ICU for a maximum of 14 consecutive days did
not resulting a reduction in the prevalence of delirium compared to placebo.
These findings do not support the routine use melatonin to prevent delirium in the critically ill.
RESIDENT’S DISCUSSION & CONCLUSIONS
Comparable baseline characteristics between the two groups
Included LOS, mortality outcomes, and use of rescue medications
GOLD standard study design
Adequately powered study, large population, less than expected loss to follow-up resulting in >95% power
Subgroup analysis with baseline delirium assessment with a priori groups
-
Brief summary of authors’
main discussion points
Alpha value of 0.05 and a power of 80%, sample size was increased by 15% to account for
potential losses to follow-up, incidences of coma, or inability to perform CAM, 850 patients with
425 patients in each arm
Poisson regression was used to compare the count of delirium and coma-free days between the
treatment groups using an offset of number of days in ICU
Hospital mortality was analyzed with Cox proportional hazards models and presented with Kaplan
Meyer curves.
17.1% of assessments were missed and around 20% were non-assessable
CAM-ICU assessments were not standard in most sites, which could explain some of the missed
assessments
Dose was on the medium to low range of studied doses
CAM scores were checked twice daily, flexibility was allowed in timing and de-sedation was encouraged
(nurse managed)
Study based in Australia.
Melatonin is not effective for prevention of delirium in the ICU so we would not be using it in the ICU
for the prevention of delirium.
I would not recommend melatonin for preventing delirium in the ICU.
Reference: Wibrow B, Martinez FE, Myers E, et al. Prophylactic melatonin for delirium in
intensive care (Pro-MEDIC): a randomized controlled trial. Intensive Care Med. 2022;48(4):414425. doi:10.1007/s00134-022-06638-9