Pro-MEDIC

19 December 2022 George Walker Intensive Care Medicine Leave a comment

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

Clinical Question

In adults with an expected ICU stay of > 72 hours, does the provision of enteral melatonin compared to placebo increase the number of delirium-free assessments within 14 days or before ICU discharge?

Background

Delirium is highly prevalent in ICU with associated increased mortality and morbidity
Melatonin concentrations are lower in those patient with delirium compared to those without
Melatonin has been shown to speed up sleep initiation and improve sleep efficiency without changing the sleep cycle
Small and predominantly single centre studies have shown a benefit of melatonin improving delirium rates; however these results haven’t been reproduced in large, multi-centre RCTs

Design

Multi-centre, randomized, placebo-controlled, double-blind trial
Randomised in 1:1 ratio via compute generated list
Stratified by site in blocks of 6
Melatonin and placebo manufactured in liquid form with identical physical characteristics
CAM-ICU assessment tool performed twice daily on all assessable patients
Sub-set of patients had serum melatonin concentrations measured 2-3 hours post administration
Local ethical approval
DMSB included a sleep physician
Sample size
- Based on prospective data from two main hospital sites involved
- 54% assessments deemed delirium free (SD 45%)
- To detect a 10% absolute increase in delirium free assessments with 80% power and alpha of 0.05 required 319 patients in each arm
- Rounded to 425 patients in each group to allow for non-parametric tests, missing data and loss to follow-up

Setting

12 ICUs in Australia
July 2016 – September 2019

Population

Inclusion:
- Adults (>18 yo)
- Admitted to ICU with an expected LOS > 72 hours
- Within 48 hours of ICU admission
Exclusion:
- Already receiving melatonin
- Pregnancy / Breastfeeding
- Expected death within 48 hours
- Treating clinician believed that a delirium assessment within the next 14 days would not be possible due to persistent neurological dysfunction
- No enteral route
- Hepatic impairment
2764 met inclusion criteria
- 1478 excluded –> 1286 eligible
- 847 enrolled
Baseline demographics similar (comparing melatonin vs placebo)
- Age: 62 vs 62
- Regular alcohol use: 34% vs 39%
- Past psychiatric presentation: 16 vs 18%
- Pre-DELIRIC score: 45.3 vs 42.7
- CAM +ve at baseline: 10% vs 8%
- Emergency ICU admission: 82% vs 80%
- Sepsis as diagnosis: 24% vs 23%

Intervention

Melatonin
- 4mg (2mls) at 21:00 for 14 nights or until ICU discharge

Control

Placebo
- 2mls of placebo at the same time

Management common to both groups

All other care at treating clinicians discretion
Staff advised to de-sedate patients as much as possible and allow flexibility in time of CAM-ICU assessment to minimise un-assessable patients

Outcome

Primary outcome:
- Number of delirium free assessments per patient: 79.2% (melatonin) vs. 80.0% (placebo); p = 0.547
  - Comparing melatonin group vs placebo group:
    - Number of assessments performed: 2975 vs 2846
    - Number of assessments per patient (median): 5 vs 6
    - Number of non-assessable time points: 19.8% vs 17.7%
    - Number of missed time points: 16.6% vs 17.7%
Secondary outcomes:
- Comparing melatonin vs placebo
- No significant difference in
  - 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%
Subgroups:
- No difference in any subgroup (Age, Sex, Baseline delirium state, ICU diagnosis and risk of delirium by pre-DELIRIC)
No adverse events in any group

Authors’ Conclusions

Enteral melatonin within 48 hours of ICU admission did not reduce the prevalence of delirium compared to placebo

Strengths

Multi-centre
Randomised
Double-blind and placebo controlled
Pre-published statistical analysis plan
Local data used in sample size calculation
Minimal loss to follow up (increases power of study)
Plausible rationale for use of melatonin and data collected to show that melatonin levels increased post administration
- Median serum concentration was 19.4 ng/ml in melatonin group vs < 0.1 ng/ml in placebo
Excellent collection of data (pharmacological and non-pharmacological therapies) that could act as confounders
Largest study to date regarding a treatment which is widely used with a mixed, limited and heterogenous evidence base

Weaknesses

Large numbers excluded. Of those screened:
- ~10% were not expected to improve within 14 days
- ~7% unable to perform CAM-ICU for preceding reason
- ~11% other
Rates of missed assessments were marginally higher than expected, and allowed for in the sample size calculation
~9% were CAM +ve at baseline
Only one dosing regime used for all patients – would a higher dose or SR release formulation be more appropriate?
- The authors provide a solid rationale for the decision to use 4mg – 10mg has been shown to have supratherapeutic day time level

The Bottom Line

This trial provides high quality evidence that although safe, 4mg melatonin does not affect rates of delirium
Interestingly sleep quantity and quality was not improved (albeit as a secondary outcome); this will make me re-consider my use of melatonin routinely

External Links

Metadata

Summary author: George Walker @hgmwalker89
Summary date: 5th December 2022
Peer-review editor: David Slessor

Picture by: nambitomo/iStock