CaffeinICU Study - A Pilot Study on the Efficacy of Oral Caffeine in Reducing the Duration of Mechanical Ventilation

Study Overview
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Brief Summary
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Background: Depressed Glasgow Coma Scale (GCS) is common among critically ill patient s in the intensive care unit (ICU). It is one of the main reasons that hampers liberation from mechanical ventilation among ICU patients. Caffeine is commonly used in neonates for the treatment of apnea of prematurity. However, its efficacy has not been established in adult population. Objective: To find out the efficacy of oral caffeine in shortening duration of mechanical ventilation among adult patients. Hypothesis: Oral caffeine is effective as a central nervous system stimulant among adult patients with depressed GCS. Study design: Multi-center, randomised, double blind, placebo controlled clinical trial Population: Adult patients (≥ 21 years old) with GCS ≤ 8 from any causes (excluding surgically reversible causes) requiring continuation of mechanical ventilation, whom acute medical issues are stable or has resolved but not suitable for extubation solely due to depressed GCS, not planned for any surgical procedures within 24 hours and not on sedative agents for at least 24 hours, will be included in this study. For patients with primary Central Nervous System (CN lesions, neurologist or neurosurgeon approval will be obtained prior to recruitment. The exclusion criteria include known allergy or adverse reactions from caffeine, pregnant women, breast-feeding women, uncontrolled cardiac arrhythmias, uncontrolled hypertension, hyperactive delirium, patients with chronic kidney disease (CKD, any stage) who received midazolam or morphine infusion, patients who received barbiturate coma, patients who are on theophylline, aminophylline or psychotropic agents at the point of screening for recruitment, patients with feed intolerant, short bowel syndrome and active seizures. Intervention: Oral caffeine citrate 5mg/kg/dose twice a day (8am, 2pm) vs placebo Outcomes: Primary - Duration of mechanical ventilation Secondary - ICU mortality, 30-days mortality, ICU length of stay, blood pressure, heart rate, incidence of arrhythmia, GCS, incidence of re-intubation and need for tracheostomy

Detailed Description
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Depressed Glasgow Coma Scale (GCS) is common among critically ill patients in the intensive care unit (ICU). It is one of the main reasons that hampers liberation from mechanical ventilation among ICU patients. Current management of this disorder focuses mainly on supportive care and treatment of the underlying disease. Directed therapies targeting neurochemical and neurotransmitter pathways are not currently available and it represents an important area of research. Caffeine is commonly used in neonates for the treatment of apnea of prematurity. It is a CNS stimulant that stimulates central respiratory drive, increases medullary respiratory center sensitivity to carbon dioxide and improves diaphragmatic contractility. However, its efficacy has not been established in adult population. Objective: The primary objective is to investigate the efficacy of oral caffeine in shortening the duration of mechanical ventilation among adult patients. The secondary objective is to investigate its relation to ICU mortality, 30-days mortality, ICU length of stay, blood pressure, heart rate, incidence of arrhythmia, GCS, incidence of re-intubation and need for tracheostomy Hypothesis: Oral caffeine is effective as a central nervous system stimulant among adult patients with depressed GCS. Proposed Trial Design: We propose a pilot multi-center, double blind, randomized controlled trial of 30 patients with depressed GCS, randomly assigned to receive oral caffeine or placebo. Planned Trial Interventions: Patients will be allocated to 2 groups (15 patients each) Oral caffeine group: patient will receive oral caffeine through their feeding tube, 5mg/kg/dose twice daily. Oral caffeine solution (colorless and odorless) will be prepared by pharmacy laboratory and supplied in amber glass bottle. Control group: patient will receive syrup BP (placebo, same diluent that is used for preparation of caffeine solution) through their feeding tube, packed and supplied in amber glass bottle by pharmacy laboratory. Oral caffeine or placebo will be initiated within 24 hours of randomization. Study intervention will be administered to patients for 3 days after recruitment or until ICU discharge, whichever comes first. The study intervention (oral caffeine) or placebo will be administered in addition to usual standards of care for ICU patients . Subject Consent and Randomization: Consent will be obtained from patient's Legally Appointed Representative(LAR) if available, or the next of kin within 72 hours following inclusion and exclusion criteria screening. The randomization system will use a computer generated randomization schedule allocating patients 1:1 to either caffeine or matching placebo by the method of permuted blocks of random undisclosed size within strata. Allocation will be random and blinded to everyone except the laboratory pharmacists who will be preparing and labelling study samples. As patients will be fed via feeding tube, they will not be able to differentiate the taste of the product. Duration of follow up: Patient clinical status will be monitored on daily basis until 30 days after recruitment or discharge from hospital, whichever earlier. Data collection: Data collection will be done prospectively.

Official Title
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CaffeinICU Study - A Randomized Controlled Multi-centre Pilot Study, on the Efficacy of Oral Caffeine, in Reducing the Duration of Mechanical Ventilation in Critically Ill Adult Patients

Conditions
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Depressed GCS, Encephalopathy

Intervention / Treatment
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* Drug: Caffeine Citrate 20 MG/ML Oral Solution
* Other: Syrup BP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (≥ 21 years old), Patients with encephalopathy (GCS ≤ 8) limiting extubation, where encephalopathy is deemed by clinician to be unresponsive to treatment or not eligible for treatment to reverse the encephalopathy (eg. transplantation) or if no treatment exists, and Patients who are not planned for any surgical procedures within 24 hours Patients who are not on sedative agents for at least 24 hours (exception for low dose fentanyl of up to 30mcg/h and dexmedetomidine of up to 0.5mcg/kg/h for analgesia/sedation/tube tolerance) For patients with primary CNS lesions, neurologist or neurosurgeon approval will be obtained prior to recruitment. Exclusion Criteria: Known allergy or adverse reactions from caffeine, Pregnant women, Breast-feeding women, Patients with uncontrolled cardiac arrhythmias, Patients with uncontrolled hypertension, Patients with hyperactive delirium, Patients with chronic kidney disease (CKD, any stage) who received midazolam or morphine infusion during their ICU stay, Patients who received barbiturate coma, Patients who are on theophylline, aminophylline or psychotropic agents at the point of screening for recruitment, Patients with feed intolerant, short bowel syndrome, or Patients with active seizures

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, randomised, double blind, placebo controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral caffeine group<br>Patients in this arm will receive treatment with oral caffeine | Drug: Caffeine Citrate 20 MG/ML Oral Solution<br>* Caffeine syrup will be prepared by pharmacy laboratory and kept refrigerated (2-8C), to be used within 1 month from the date of preparation by pharmacy laboratory.<br>* Other names: Caffeine;|
| Placebo Comparator: Control group<br>Patients in this group will receive syrup BP (placebo) | Other: Syrup BP<br>* Syrup BP will be prepared by pharmacy laboratory and kept refrigerated (2-8C), to be used within 1 month from the date of preparation by pharmacy laboratory.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of mechanical ventilation | Duration of mechanical ventilation in days | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU mortality | Mortality in the ICU (yes or no) | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| 30-days mortality | Mortality within 30 days (yes or no) | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| ICU length of stay | Length of ICU stay in days | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| Blood pressure | Blood pressure in mmHg | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| Heart rate | Heart rate in beats per minute | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| Incidence of arrhythmia | Incidence of arrhythmia reported (yes or no) | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| GCS | Glasgow coma scale | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| Incidence of re-intubation | Need for re-intubation following an extubation (yes or no) | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| Incidence of terminal extubation | Terminal extubation in the ICU (yes or no) | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 
| Need for tracheostomy | Need for tracheostomy (yes or no) | From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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caffeine, depressed GCS, mechanical ventilation