Nishikimi
Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in ICU
Nishikimi. Critical Care Medicine 2018; published online doi: 10.1097/CCM.0000000000003132
Clinical Question
- In critically ill adults, does the administration of ramelteon compared to placebo reduce the length of intensive care stay?
Background
- Melatonin is a hormone excreted by the pineal gland with regulatory effects on circadian rhythm and possibly antioxidant and anti-inflammatory effects
- Exogenous melatonin has been shown to improve sleep quality and reduce delirium, but little research has been conducted specific to Intensive Care Unit patients
Design
- Single centre, randomised, controlled trial
- Recruitment by consequetive sampling of admissions to 10 bed emergency medical Intensive Care Unit (ICU)
- Randomisation in 1:1 ratio prepared by “an outsider”, stratified by age, APACHE 2 score and intubation status in block sizes of four
- Allocation concealment is not described
- Patients, clinicians and statisticians were all blinded to the allocation
- Intention-to-treat statistical analysis
- Primary outcome was length of stay (LOS) in ICU
- Due to non-normal (right skew) distribution of LOS data, the authors chose to apply log-transformation to approximate a normal distribution
- Once transformed, Student’s t test was used to compare two means
- Power calculation performed a priori
- Clinically important reduction in length of stay (LOS) defined as one day
- Power 80% (20% probability of false negative conclusion)
- Significance level 0.05 (5% probability of false positive conclusion)
- Required sample size of 182 patients
Setting
- Single centre in Nagoya, Japan
- 10 bed Emergency and Medical ICU
- Surgical ICU separate unit
- May 2015 – April 2017
Population
- Inclusion: Adults (≥20 years); able to recieve medication enterally (oral or via nasogastric tube) during first 48 hours of admission
- Exclusion: Withheld consent; allergy to ramelteon; prior administration of ramelteon or fluvoxamine (potential drug interaction)
- 98 patients screened; 92 randomised (6 excluded due to lack of consent); 88 included in modified intention-to-treat (4 discharged from ICU without receiving any study drug [2 in each group])
- Baseline demographics were similar – authors highlighted some imbalances but since P-values were all > 0.05 it is unlikely these differences were due to an improper randomisation process (Ramelteon group vs Control group; * = intentionally balanced through stratification of randomisation)
- Median age*: 68 years vs 68 years
- Mean APACHE 2*: 23.98 vs 23.95
- Mechanical ventilation*: 40.0% vs 46.5%
- Sex: ♂ 73.3% | ♀ 26.7% vs ♂ 55.8% | ♀ 44.2% (P = 0.12)
- Existing dementia: 13.3% vs 2.3% (P = 0.11)
- Diagnosis of sepsis: 26.7% vs 20.9% (P = 0.62)
- Heavy alcohol use:6.7% vs 2.3% (P = 0.62)
- Pre-admission psychiatric or sleeping medication: 5.0% vs 7.2% (P = 0.57)
Intervention
- Ramelteon
- 8 mg administered at 8pm daily until ICU discharge
Control
- Placebo
- 1 g lactose powder indistinguishable from study drug administered at 8pm daily until ICU discharge
Management common to both groups
- Bedside nurses and clinicians were unaware of allocation and encouraged to treat all patients equally
- Delirium prevention was standardised
- Avoidance of unnecessary mobilisation
- Limitations to family visits (11am–12pm; 3pm–4pm)
- Low lighting and sound level after 10pm
- Treatment of delirium was standardised
- Primarilily using non-pharmacological approach
- Early mobilisation
- Comfortable and sleep-conducive environment
- Treatment of pain, dyspnoea and anxiety
- Risperidone (1 mg) or dexmedetomidine (up to 0.7 ug/kg/hr) at clinicians’ discretion
- Haloperidol 5 mg IV as last resort
- Decision to discharge from ICU was made by a multidisciplinary group at a twice daily meeting based upon:
- No / minimal sedation required
- Oxygen saturation > 90% requiring less than FiO2 0.5
- No mechanical ventilation
- No / minimal inotropic or vasopressor support
- Urine output > 0.5 ml/kg/hr
- No need for renal replacement therapy
- Delirium assessed using CAM-ICU
- Sedation level assessed using Richmond Agitation Sedation Scale (RASS)
Outcome
- Primary outcome: duration of intensive care length of stay was shorter in the Ramelteon group compared to the Placebo group
- Ramelteon group: median 4.56 days (range 2.10 – 7.07)
- Placebo group: median 5.86 days (range 2.97 – 14.16)
- Median difference: 1.3 days
- P-value (after log-transformation) = 0.082
- After a pre-specified multivariate analysis, administration of Ramelteon was independently associated with a statistically significant reduction in length of stay
- P-value = 0.028
- Secondary outcome:
- Delirium occurred less frequently in the Ramelteon group
- Ramelteon 24.4% vs Placebo 46.5%
- OR: 2.69 (95% CI 1.09 to 6.65; P = 0.044)
- ARR: 22.07% (95% CI 2.58% to 41.56%)
- NNT: 5
- Fragility Index: 1
- Duration of delirium was shorter in the Ramelteon group
- Mean 0.78 days vs 1.40 days (P = 0.048)
- In-ICU mortality did not differ between the groups
- Ramelteon 6.7% vs Placebo 7.5%
- ARR: 0.31% (95% CI -10.23% to 10.85%; P = 1.0)
- Quality of sleep was better in the Ramelteon group
- Fewer awakenings per night (0.8 awakenings vs 1.31 awakenings; P = 0.045)
- More nights without awakenings (51% vs 30%; P = 0.048)
- No difference in mean hours of sleep (7.29 hrs vs 6.78 hrs; P = 0.252)
- Delirium occurred less frequently in the Ramelteon group
Authors’ Conclusions
- Administration of Ramelteon to ICU patients was associated with a “tendency toward a decreased duration of ICU stay”, and a decrease in the incidence and duration of delirium that reached statistical significance
Strengths
- Sensible theory and testable hypothesis
- Appropriate outcome measure relevant to hospital resource use and patients, investigating the overall multi-modal effect of melatonin-receptor agonism
- Balanced baseline variables suggest the randomisation process was unbiased, despite the concerns about sequence generation and allocation concealment described as weaknesses below
- Good blinding of all relevant individuals
- Primary outcome was guided by criteria and multidisciplinary input to reduce subjectivity
- Statistical manipulation and analysis was appropriate to the data type
- Clinically important difference was defined a priori
Weaknesses
- Massive under-recruitment has reduced the statistical power of the conclusion of this trial
- A false negative conclusion may have been drawn
- The manuscript reports that fewer patients than expected met the inclusion criteria
- The number of patients screened and the reasons for not meeting the inclusion criteria are not provided
- Method for construction of randomisation sequence is not clearly defined
- Was it computer generated or was a simpler but possibly biased method used?
- Concealment of allocation not described
- Was the randomisation sequence hidden adequately prior to patient allocation?
- Maintenance of allocation not reported
- Did all patients receive intended drug and were they otherwise treated the same?
- Single centre and medical only ICU design may limit the external generalisability beyond the scope of medical emergencies in Japan
The Bottom Line
- This is a promising trial that adds to the growing evidence of benefit from administration of melatonin and melatonin-receptor agonists
- Despite concern about some of the methods, the overall conduct of this trial is good and I believe the internal validity is good enough to accept the results as accurate
- However, the small sample size and single centre design limits the generalisability and I shall await larger trials before recommending melatonin or ramelteon to all critically ill patients
External Links
- [article] Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU
- [further reading] Sleep and ICU by LITFL
- [further reading] Simons (Light and ICU Delirium) by The Bottom Line
Metadata
Summary author: Duncan Chambler
Summary date: 11 April 2018
Peer-review editor: Adrian Wong