Safety and efficacy of analgesia-based sedation using remifentanil versus standard hypnotic-based regimens in intensive care unit (ICU) patients with brain injuries: a randomised, controlled trial

ISRCTN	ISRCTN50308308
DOI	https://doi.org/10.1186/ISRCTN50308308
Secondary identifying numbers	USA30217

Submission date: 24/05/2004
Registration date: 25/05/2004
Last edited: 08/09/2008

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Injury, Occupational Diseases, Poisoning

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Andreas Karabinis
Scientific

Intensive Care Unit
Genimatas General Hospital
Athens
Greece

Study information

Study design	Randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Scientific title
Study objectives	To compare the safety and efficacy of analgesia-based sedation with conventional hypnotic-based sedation in patients with brain injuries requiring sedation during mechanical ventilation.
Ethics approval(s)	Not provided at time of registration.
Health condition(s) or problem(s) studied	Neurotrauma
Intervention	The study was designed to compare the safety and efficacy of analgesia-based sedation, using remifentanil, with conventional hypnotic-based sedation in patients with brain injuries requiring sedation during mechanical ventilation. Patients were randomised on a 2:1:1 basis to receive either an analgesia-based treatment regimen or a hypnotic-based treatment regimen: 1. Analgesia-based treatment regimen (n = 84): remifentanil was initiated and titrated to provide optimal sedation and analgesia before the addition of a hypnotic agent, according to a predefined dosing algorithm 2. Hypnotic-based treatment regimen: patients received the opioid fentanyl (n = 37) or morphine (n = 40) and a hypnotic agent for analgesia and sedation which were administered simultaneously and then titrated to response For all three treatment groups, on days 1 - 3 the hypnotic agent was propofol, on days 4 - 5 propofol was substituted with midazolam. Patient monitoring: All patients were intensively monitored throughout the study. Baseline Glasgow Coma Score (GCS), SAS, Pain intensity (PI), mean arterial pressure (MAP) and heart rate (HR) were recorded prior to the administration of study drugs. When available, intra-cranial pressure (ICP) and cerebral perfusion pressure (CPP) were also recorded. SAS, PI, MAP, HR, ICP and CPP were then recorded at the time of any changes in study drug infusion rates or bolus dosing and at 10 minute intervals afterwards until adequate SAS/PI scores were attained. Once target SAS and PI scores were attained, haemodynamic monitoring was performed at 1 - 4 hour intervals. In addition, haemodynamic parameters were recorded at the start of down-titrations of study drugs for neurological assessment of patients and when the assessments were completed. The SAS, PI, MAP, HR, ICP and CPP were also recorded at the start of and at the time of adequate transitioning from propofol to midazolam at the end of day 3 and if a patient was extubated before day 5 of the study treatment period. These parameters were also recorded at the start of the final transition to an alternative analgesia/sedation regimen at the end of study day 5, at 20 min intervals after each down-titration of the remifentanil infusion as part of this process, at 30 and 60 min after the termination of the infusion and at final transition to an alternative opioid. Patients were continuously assessed for the occurrence of adverse events until 24 hours after permanent discontinuation of the study drugs or until ICU discharge if this occurred earlier. Serious adverse events were defined as adverse events that resulted in any of the following outcomes: death, life-threatening event, prolongation of hospitalisation, a disability/incapacity. Important medical events which did not result in death or were not life-threatening, were considered serious adverse events when, based upon appropriate medical judgement, they jeopardised the patient and required medical or surgical intervention to prevent one of the outcomes listed above.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Remifentanil, fentanyl
Primary outcome measure	Not provided at time of registration.
Secondary outcome measures	Not provided at time of registration.
Overall study start date	01/01/2004
Completion date	31/12/2004

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	161
Key inclusion criteria	1. Acute, severe neurological insult/injury 2. Elective or emergency neurosurgery 3. Aged 18 - 80 years 4. Weighed less than or equal to 120 kg 5. Admitted into the ICU within the past 24 hours, were intubated and were expected to require mechanical ventilation for 1 - 5 days
Key exclusion criteria	1. Had or were likely to require: 1.1. Long-acting (or continuous administration of) neuromuscular blocking drugs to facilitate mechanical ventilation during the study period 1.2. Barbiturate administration prior to or during the study period 1.3. Epidural block during the maintenance or extubation phases of the study 2. Failed to demonstrate signs of recovery/responsiveness within 6 hours of stopping any analgesia/sedation regimen in use at the time of screening for study entry 3. Likely to require a tracheostomy with spontaneous ventilation within five days of starting study drug treatment 4. Suffered severe, associated traumatic injury, had a neurological condition that might affect the ability to assess their Sedation-Agitation Scale (SAS) score, were admitted for status epilepticus, had moderate or severe renal impairment (predicted creatinine clearance of less than 50 ml/min) 5. History of allergy to opioids, benzodiazepines, propofol or of alcohol/drug abuse 6. Pregnant or lactating women
Date of first enrolment	01/01/2004
Date of final enrolment	31/12/2004

Locations

Countries of recruitment

Austria
Belgium
Germany
Greece
Netherlands
Spain

Study participating centre

Intensive Care Unit

Athens
Greece

Sponsor information

GlaxoSmithKline (UK)
Industry

Greenford Road
Greenford
UB6 OHE
United Kingdom

"ROR"	https://ror.org/01xsqw823

Funders

Funder type

Industry

GlaxoSmithKline (UK)
Government organisation / For-profit companies (industry)

Alternative name(s): GlaxoSmithKline plc., GSK plc., GSK
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	Results	01/08/2004		Yes	No