medical critical care

1. PROPHYLACTIC MELATONIN FOR DELIRIUM
IN INTENSIVE CARE (PRO-MEDIC):
A RANDOMIZED CONTROLLED TRIAL
B WIBROW. INTENSIVE CARE MEDICINE 2022. DOI: 10.1007/S00134-022-06638-9
PRESENTER: DR DILEEP N
MODERATOR: DR PRASOON GUPTA

2. BACKGROUND
• Delirium is a condition of acute organic brain dysfunction with fluctuating
disturbances of attention and cognition.
• Prevalence in intensive care units (ICUs) has been reported up to 80%
• Highly distressing for patients and families and commonly reported as the
worst experience of an ICU admission
• Associated with universally poorer outcomes including higher mortality rate
and increased ICU and hospital length of stay (LOS), increased duration of
mechanical ventilation, need for physical restraints, poorer functional status,
cognitive impairment, increased admission to residential care, and increased
medical costs

3. • Best practices currently include optimizing analgesia, minimizing sedation,
and non-pharmacological strategies such as early mobilization.
• No pharmacological agent has been convincingly shown to prevent delirium in
the ICU till date.

4. • Melatonin, a serotonin-derived hormone secreted by the pineal gland,
regulates the sleep cycle and its administration improves sleep quality and
duration in non-critically ill patients.
• Poor sleep and dysregulated melatonin production are implicated in the
pathogenesis of delirium in the ICU.
• Serum melatonin concentrations are lower in patients with delirium in critical
care, geriatric, and post-surgical settings compared with a non-delirious
patient.
• Melatonin has anti-inflammatory and immunomodulatory properties that
may be neuroprotective in brain injury, encephalopathy, and
neurodegenerative disease.
• It is also safe, inexpensive, and widely used in the community, making it an
attractive intervention for delirium prevention.

5. AIMS AND OBJECTIVES
• This study aimed to determine the effect of melatonin administration on
delirium prevalence in critically ill patients.
• Primary objective: To determine whether melatonin given prophylactically
decreases the prevalence of delirium in critically ill patients.
• Secondary objectives: To determine whether prophylactic melatonin
decreases the severity and duration of delirium, improves sleep quality,
reduces hospital and ICU LOS, improves morbidity and mortality, and reduces
healthcare costs through reduced LOS and intensity of medical therapy.

6. MATERIAL AND METHODS
• Prospective
• Multi-centric
• Randomized
• Placebo-controlled
• Double-blind
• Prophylactic intervention trial

7. • Ethical approval approved from the Institutional Ethics Committee.
• Prospectively registered with the Australian and New Zealand Clinical trials
registry.
• Patients or legally authorized representatives provided written informed
consent.
• A data safety monitoring committee (DSMC) comprising an independent ICU
specialist, epidemiologist and sleep physician, and an independent statistician
oversaw the trial.

8. PATIENT POPULATION
• This study was conducted in ICUs of 12 participating hospitals in Australia.
• Patients aged 18 years or older who required ICU admission with an expected
LOS greater than 72 h were eligible if enrolled within 48 h of ICU admission.
• Received the first dose of the study drug on the day on enrolment.

9. EXCLUSION CRITERIA
• Patients already receiving Melatonin.
• Prior hypersensitivity reaction to study drug components.
• Expected death within 48 hours.
• Pregnant and breastfeeding patients.
• Non-English-speaking patients.
• Patients in whom the treating clinician believed a delirium assessment within the next 14
days would not be possible due to persistent neurological impairment.
• Patients not on enteral route of feeding.
• Hepatic impairment (alanine aminotransferase >500 IU/L, liver transplant, or Child–Pugh B/C
liver cirrhosis)

10. ALLOCATION AND RANDOMISATION
• Patients were randomized to melatonin or placebo (1:1 ratio) via a computer-
generated randomization list, stratified by site, with standard block sizes of six.
• The list was generated and managed by a statistician independent of the study and
provided directly to the compounding pharmacy.
• Each patient’s bottle was labeled with a site-specific randomization number, which
became their study number.
• Melatonin and placebo were manufactured in liquid form, identical in appearance,
taste, and smell.
• Clinical staff, investigators, trial statisticians, and patients remained blinded. The
statisticians were unblinded only after the statistical plan was finalized, data
collection completed, and the database locked.

11. TRIAL INTERVENTION
• Eligible participants were randomized to receive 4 mg (2mls) of melatonin or placebo
(via oral or nasogastric tube) at 21:00 h for 14 consecutive nights or until ICU
discharge, whichever occurred first.
• All other care was as per the treating clinician’s discretion.
• Open-label prescription of melatonin was discouraged and recorded as a protocol
violation.
• Serum melatonin concentrations 2–3 h post-administration were measured in a
subset of patients (convenience sample) by a blinded, independent biochemist.
• Compliance was checked daily, indicated by nursing signatures on the medication
chart confirming administration.

12. OUTCOMES
PRIMARY OUTCOME: Difference in the proportion of delirium-free assessments,
as a marker of delirium prevalence, within 14 days or before ICU discharge
between the two groups.
SECONDARY OUTCOMES:
• Overall prevalence of delirium
• Duration of delirium
• Severity of delirium

13. • Delirium was measured using the Confusion Assessment Method for ICU
(CAM- ICU) score.
• Indirect markers of delirium severity were also recorded daily until ICU
discharge or day 14 after enrolment. These were:
(1) need for anti-psychotics or sedation (total daily doses)
(2) need for physical restraints
(3) patient participation in physiotherapy sessions and mobilisation
(4) patient removal of intravenous lines, drains or catheter

14. • The CAM-ICU assessment was performed twice daily (12 hourly) on all assessable
patients over the study period.
• To capture any indirect benefits of melatonin on the consequences of delirium and
sleep, rescue therapies for delirium, sleep assessments, LOS (ICU and hospital) and
mortality as secondary outcomes with a follow-up of 90 days.
• All serious adverse events (SAEs) were defined and reported.
• Melatonin undergoes hepatic metabolism, and as a safety measure, liver function
tests were measured at baseline and day 5.
• Sleep was measured daily using the Richards–Campbell Questionnaire performed by
the patient and/or bedside nurse. The Little’s sleep questionnaire, 2–14 days post-
ICU discharge, tested the patients’ recollection of sleep.

15. STATISTICAL ANALYSIS
• Prospective data from 100 patients meeting the eligibility criteria were
collected from the two main hospital sites to guide sample size calculation.
• To detect a 10% absolute increase (80% power and alpha value of 0.05) in
delirium-free assessments, 319 patients in each group were needed.
Adjustments for using non-parametric tests (15%) increased this to 367.
• To account for missing data or loss to follow-up, the sample size was increased
a further 15% to 423 per group and rounded to 425 for a total of 850
patients.

17. • Trial was analyzed comparing melatonin to placebo groups using an intention-
to-treat approach.
• The primary outcome, the difference in the proportion of delirium-free
assessments, was analyzed using Mann– Whitney U test.
• Delirium was also examined, categorizing patients as having or not having
experienced delirium during the study using univariate logistic regression.
• Univariate logistic regression was also used to examine binary outcomes
including medications, non-pharmacological delirium treatments, mechanical
ventilation, and ICU mortality.
• Hospital mortality within 90 days was analyzed using Cox proportional
hazards models and presented using Kaplan–Meier curves.
• Statistical analysis performed using Stata V15 (StataCorp LLC)

20. RESULTS
• Delirium assessment was attempted at 82.9% of all available time points, with 17.1% of the
assessments missed. The median number of assessments per patient was 5 (melatonin
group) and 6 (placebo group), respectively.
• Of all time points assessed, 78.7% of assessments were delirium-free, with no significant
difference between participants who received melatonin (79.4%) or placebo (77.9%)
• There was no significant difference in the proportion of delirium-free assessments per patient
between melatonin (79.2%) and placebo (80%) groups (p=0.457).
• There was also no difference in total patients free from delirium or coma throughout the
study [193 (46.1%) vs 216 (51.2%)].
• In the longitudinal analysis (including and excluding coma), there was no significant effect of
treatment or an interaction between treatment and time, with or without adjustment for age
and gender.

21. • The use of melatonin was not associated with differences in mechanical
ventilation duration, LOS, ICU readmission, or mortality when compared to
placebo.
• There was no difference in the utilization of non-pharmacological therapies
commonly part of delirium prevention strategies or sleep hygiene
management: physiotherapy participation, trips out of ICU, music therapy,
masks, and ear plugs.
• The average daily observed sleep in both groups in ICU was less than 6 h a
night. When patients were interviewed after ICU discharge, the average
estimation was less than 4 h. The rating of quantity and quality of sleep
during ICU recalled by patients in both groups was low.
• There was no difference in any measures of sleep quality or quantity between
the two groups

22. • Average percentage of delirium free days: 79.5% vs. 80.2%
• Average percentage of delirium and coma free days: 64.2% vs 67.6%
• Participants with delirium: 35.1% vs 32.7%
• No difference in sleep quantity or quality
• > 40% in both groups had sleep quality and quantity rated as poor or very
poor
• Requirement for anti-psychotics: 21.2% vs 19.4%
• ICU LOS: 5 vs 5 days
• Hospital LOS: 14 vs 12 days
• 90-day mortality: 15.5% vs 15.6%

23. • There was no difference in the use of antipsychotics, benzodiazepines, or
physical restraints.
• For hospital mortality, the hazard ratio was 1.03 (95%CI 0.70–1.51, p=0.875)
• In 17 patients (12 melatonin, 5 placebo), the median serum melatonin
concentration 2–3 h after administration was 19.4 ng/ml (interquartile range:
4.7–52.6) in the melatonin group and <0.1ng/ml in the placebo group. These
levels are consistent with the findings of other studies involving
administration of exogenous melatonin.
(normal endogenous concentrations range from 0.002 to 0.2 ng/ml)

26. SUBGROUP ANALYSIS
• The results of sub-groups in terms of the primary outcome largely reflected
the whole cohort, with most having no difference between the two groups.
• 521 patients were negative for delirium at baseline and there was no
difference in the primary outcome in this subgroup.
• There was no difference with greater exposure to the study intervention with
no treatment effect seen when only those >7 days (>7 doses) were evaluated.

28. • No patients suffered SAEs as defined by the protocol.
• There were no differences in liver function tests at day 5.
• Due to the lack of any significant differences, the planned cost consequence
analysis was not conducted.
• There were no specific reasons identified for missing delirium assessments.
Prior to the study, CAM-ICU assessments were not routine practice at most
study sites which could explain this.

29. DISCUSSION
• In this multi-centre, double-blinded, placebo-controlled, randomized clinical trial conducted
in 12 Australian hospitals, the use of melatonin was not associated with an increase in the
proportion of delirium-free assessments in critically ill patients.
• Critically ill patients are at high risk of delirium, and hence, any potential benefit of melatonin
may be more evident in this population.
• This study was consistent with previous work showing critically ill patients had absent or
negligible melatonin levels and enteral melatonin was successfully absorbed.
• The dose of 4 mg was selected as trials of similar doses (0.5–5 mg) had reported benefit, an
excellent safety profile and avoided daytime sedation.
• In this trial, 4 mg of melatonin led to high plasma levels when melatonin levels would
typically be elevated in a healthy population.

30. • Bourne et al. and Gandolfini et al. both evaluated 10 mg of melatonin in ICU
and reported improved sleep quality but not duration, with Bourne et al.
reporting daytime supratherapeutic levels.
• de Jonghe et al., evaluated 452 patients undergoing acute hip surgery,
reported no reduction in delirium with 3 mg of melatonin daily versus placebo
for 5 days.
• Although illness severity and heterogeneous diagnoses may make it more
difficult to demonstrate a benefit of melatonin on delirium, the lack of any
treatment effect in any of the a priori subgroups refutes this concern.

31. • ICU is a particularly stimulating environment with noise, artificial light, and
potential interventions overnight, which may mask effects of sleep hygiene
treatments. Melatonin could be investigated as part of a bundle tackling
multiple reasons for poor sleep in ICU.
• The use of antipsychotics in 20% of patients (despite limited evidence of
effectiveness till date, and physical restraints in almost 15% of patients is of
interest. This emphasizes the challenges of delivering safe and effective care
for agitated patients.
• Effective evidence-based delirium therapies are limited to preventative
strategies and bundles of care (e.g., ABCDEF bundle) that include non-
pharmacological interventions such as frequent re-orientation, early
mobilization, exposure to sunlight, and sleep hygiene.

32. STRENGTHS OF THE TRIAL
• Largest randomized control trial of melatonin for delirium prevention to date.
• Multi-center, double-blinded, placebo-controlled.
• Pre-published statistical analysis plan.
• All patients analyzed had follow-up data for mortality and LOS (minimal loss to
follow-up).
• Plausible rationale for use of melatonin and data collected to show that
melatonin levels increased post administration.
• Excellent collection of data (pharmacological and non-pharmacological
therapies) that could act as confounders.

33. LIMITATIONS OF THE TRIAL
• The intervention and primary outcome assessment were limited to ICU which may
limit the ability to detect longer term effects of melatonin thereby reducing
generalizability.
• The rate of delirium-free assessments was higher than anticipated and there were
missing delirium assessments in 17.1%.
• The sample size was increased by 15% to account for missing data and non-
assessable time points, but this may have been insufficient.
• Although confirmation of enteral absorption was demonstrated, the dose may still
have been too low or there may be more appropriate dosing strategies than a single
immediate release formulation. Slow-release formulations have been studied, and a
novel dosing-regime of a loading dose followed by supplemental smaller doses over-
night has been described and may warrant further investigation.

34. CONCLUSION
Using melatonin early and continued throughout the ICU for a
maximum of 14 consecutive days did not result in a reduction in the
prevalence of delirium compared to placebo.
These findings do not support the routine use of melatonin to
prevent delirium in the critically ill.