Oral Melatonin in Critically Ill High-risk Patients

Randomized, Controlled, Double Blind Trial to Evaluate Sedation and Quality of Life in High-risk, Critically Ill Patients Treated With Oral Melatonin

Sleep disruptions are extremely common in high-risk critically ill patients. The investigators want to analyse oral melatonin potentialities as a sedative and a free-radicals scavenger for critically ill patients, and secondarily for preventing Delirium during their ICU stay and post-traumatic stress disorders after ICU discharge.

Study Overview

• Status: Completed
• Conditions: Mechanically Ventilated Patients; Critically Ill Patients
• Intervention / Treatment: Drug: Placebo; Drug: Oral melatonin 3mg BID

Detailed Description

The physiological secretion of such melatonin follows a circadian rhythm: melatonin plasma concentration increases with the dark reaching a peak around to midnight and then gradually decreases (Reiter, 1996; Shigeta et al., 2001; Kunz et al., 2004; Brzezinski et al., 2005).

Administration of oral melatonin could be useful in critically ill high-risk patients in Intensive Care Units because these patients are often suffering from sleep disturbances (Weber et al., 1985; Bourne and Mills, 2004) possibly because of:

• presence of underlying pathology with pain and anxiety,
• presence of oral or nasal respiratory prosthesis,
• execution of therapeutic procedures on 24 h. Moreover it has been demonstrated that in ICU patients melatonin rhythm is desynchronized (Bourne and Mills, 2000). This is probably related to sedation and-or mechanical ventilation. Furthermore, it has been showed that melatonin is a powerful anti-oxidant, therefore it could be potentially useful in critical patients usually characterized by increased production of oxygen free radicals.

AIM OF THE STUDY The study is aimed to estimate if the administration of oral melatonin in ICU patients is able to regularize the sleep-waking rhythm, improving sleep quality and reducing episodes of agitation/mental confusion. The main objectives are: assessment of sleep quality, prevalence of mental confusion/agitation, amount of daily sedative drugs administered and modification of redox status.

ENROLLMENT OF PATIENTS At the admission in ICU, obtained the informed consent, the patients will be randomly assigned to the "Treatment" group receiving melatonin 3mg BID by oral route (or nasogastric tube) or to the "Control" group receiving placebo. The sedation will be performed according to clinical standard.

EXPERIMENTAL PROTOCOLS

The following parameters will be monitored:

• epidemiological data,
• quality of the sleep estimated by wrist actigraphy,
• EEG profile on 24h in order to estimate the distribution of sleep phases,
• diurnal and nocturnal hours of sleep,
• total amount of sedative drugs during 24 hours, particularly during nocturnal sedation,
• assessment of sedation level (RASS) (Sessler et al., 2002; Ely et al., 2003),
• episodes of psychomotor agitation and mental confusion (CAM-ICU) (Ely, 2001; 2004),
• evaluation of blood redox state (GSH, GSSG, GSH/GSSG),
• adverse events.

AT THE DISCHARGE FROM ICU, evaluation of:

• SCID-I and SCID-II (Structured Clinical Interview for DSM),
• CAPS (Clinician Administered PTSD Scales),
• HAM-A and HAM-D (Hamilton Rating Scales for Anxiety and for Depression),

• completion of the module for the stressors in ICU and for the transcription of the dreams.

  3 MONTHS AFTER DISCHARGE FROM ICU, evaluation of:

• SCID-I and II,
• CAPS,
• HAM-A and HAM-D,
• TAT (Thematic Apperception Test),
• completion of the module for the stressors in ICU and for the transcription of the dreams.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20142
    • Azienda Ospedaliera San Paolo - Polo Universitario

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• High Treatment > 1 day
• Normal gastrointestinal function

Exclusion Criteria:

• Status asthmaticus
• Chronic renal failure under dialytic treatment
• Severe hepatopathy (Child-Pugh class = C)
• Comatous patients (GCS < 12)
• Head trauma, severe neurological diseases (ictus cerebri, SAH, ...)
• Intoxicated patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: A - placebo; Identical tablets without the active principles. Each evening, nurses are requested to give 2 tablets at 8 PM and 12 PM	Drug: Placebo; Identical tablets without the active principles. Each evening nurses are requested to give 2 tablets at 8 PM and 12 PM
ACTIVE_COMPARATOR: B - melatonin; Identical tablets containing melatonin 3 mg Nurses are requested to give two tablets daily, at 8 PM and 12 PM.	Drug: Oral melatonin 3mg BID; Identical tablets containing melatonin 3 mg. Nurses are requested to give two tablets daily, at 8 PM and 12 PM; Other Names: MELATONIN 3 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall sedatives daily doses	Discharge from ICU

Secondary Outcome Measures

Outcome Measure	Time Frame
Prevalence of Delirium assessed with CAM-ICU	Discharge from ICU
Prevalence of mental disorders	60 days after ICU discharge
ICU length of stay	Discharge from ICU
ICU mortality	Discharge from ICU
Hospital mortality	Hospital discharge
Sleep quantity assessed by wrist actigraphy	Discharge from ICU

Collaborators and Investigators

• Sponsor: University of Milan
• Investigators: Study Chair: Gaetano Iapichino, MD, University of Milan

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (ACTUAL): April 1, 2010
• Study Completion (ACTUAL): May 1, 2010

Study Registration Dates

• First Submitted: May 4, 2007
• First Submitted That Met QC Criteria: May 4, 2007
• First Posted (ESTIMATE): May 8, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): July 28, 2010
• Last Update Submitted That Met QC Criteria: July 26, 2010
• Last Verified: January 1, 2010

More Information

Terms related to this study

• Keywords: melatonin; ICU; sedation; actigraphy; critical patients
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: Mela-UniMi-0001