A Phase IV Study Investigating the Effects of Remifentanil Concentrations on Propofol Requirements for Loss of Consciousness, Response to Painful Stimuli, Bispectral Index and Associated Haemodynamic Changes
Condition: Induction of Anaesthesia
MeSH terms: Unconsciousness
Study type: Interventional
Phase: Phase 4

Summary: 
      A prospective, randomised, phase IV trial including 150 patients.

      To evaluate the effects of varied concentrations of remifentanil on the proposal requirements
      for the loss of consciousness and response to pain and to evaluate the haemodynamic changes
      and processed EEG (BIS) during induction of anaesthesia.
    

Detailed description: 
      BackGround

      The combination of remifentanil and propofol infusions is a widely used method of total
      intravenous anaesthesia. (1) Target controlled infusion (TCI) is a pharmacokinetic (PK)
      infusion system using data from a large population of patients to calculate and deliver
      stable concentrations of a drug based on a three compartment PK model. Both propofol and
      remifentanil are ideal drugs for delivery in this way because of their quick distribution,
      metabolism and excretion. (2) Remifentanil is a potent synthetic opioid receptor (MOR)
      agonist with a short recovery irrespective of the duration of its administration. This is due
      to it being quickly broken down by non-specific esterases in blood and tissues. (3)
      Remifentanil like all opioids is not very hypnotic in clinically relevant concentrations. (4)

      Remifentanil has been shown to reduce propofol requirements during induction and maintenance
      of anaesthesia. (5)(6) Also modest doses of remifentanil markedly reduce the amount of
      propofol required to ablate response to painful stimuli. The relationship between propofol
      and remifentanil has been reported as synergistic but additive when using propofol
      concentrations within the clinical range. (7)(8) However in other studies, BIS has shown no
      interaction between propofol and remifentanil (9)(10) A correlation between BIS, painful
      stimuli and other opioids has been demonstrated. (11) It has been suggested that BIS values
      can change with propofol and painful stimuli and this can aid administration of remifentanil
      in a dose dependent manner. (12) Since propofol and remifentanil are ubiquitously used
      together, the interaction between these drugs and EEG needs to be defined in more detail.

      Trial Objectives To see whether remifentanil affects the dose of proposal required for loss
      of consciousness and loss of response to painful stimuli and whether this is reflected in
      changes in brain EEG (bispectral index BIS)

      Hypothesis That the effect site concentration of proposal at loss of consciousness will only
      be moderately affected by concurrently remifentanil infusion but BIS will not change. That
      the clinical response to painful stimuli will markedly decrease when there is concurrent
      infusion of remifentanil. With painful stimuli there will be an increase in BIS but this will
      be blocked by remifentanil.

      Methodology From the start date of the study, the first 100 patients eligible will be
      included. Patients will be allocated into one of two groups, group A or group B by a computer
      generated randomization table.

      For each patient, after receiving written consent, the patient will enter the theatre where
      they are going to have their elective operation. Standard anaesthetic monitoring will be
      applied, plus a BIS monitor. External peripheral nerve stimuli electrodes will be placed over
      the ulner nerve on the dominant arm. IV access will be gained by the anaesthetist. All
      infusions will run through the same IV cannula using standardized one way valves.

      One anaesthetist will look after the air way while the second anesthetist or a research
      assistant will fill in the data collection sheet and determine point of loss of consciousness
      and point of loss of response to painful stimuli. The air way anesthetist will know by a
      sealed envelope whether the patient is on group A or B. For the patients in group A, the
      remifentanil infusion, using the minto effect site concentration model, will be set at
      0ng/ml. For the patients in group B the remifentanil infusion will be set at 3ng/ml. After 5
      minutes the propofol infusion will commence, using the Marsh effect site concerntration TCI
      model, at 1mcg/ml and will be increased by 0.2mcg/ml every one minute. Heart Rate, blood
      pressure and BIS number will be recorded every minute. Every 30 seconds the anaesthetist will
      prompt the patient with the vocal stimuli "say your name" in a constant tone and volume. Loss
      of consciousness will be defined as the point at which the patient fails to respond to the
      vocal stimuli and light tactite stilulation. At this point BIS, heart rate, blood pressure
      and propofol effect site concentration will be recorded.

      After loss of consciousness, a tetanic stimuli will be applied using the peripheral nerve
      stimulator and repeated every thirty seconds. The propofol infusion will continue to be
      increased every one minutes by 0.2mcg/ml. Loss of response to painful stimuli will be defined
      as the point at which the patient fails to make a withdrawal motion from the tetanic
      stimulation. Here, heart rate, blood pressure BIS number and propofol effect site
      concentration will be recorded.

      After loss of response to painful stimuli the study is complete, no further date will be
      collected, the peripheral nerve stimulator will be removed, the anaesthesia will continue and
      surgery will commence as usual.
    

Intervention name(s): Remifentanil; Propofol; Bispectral index
Intervention type(s): Drug; Drug; Other
Intervention description(s): short acting opiate; hypnotic drug; electroencephalograph
Intervention MeSH terms: Remifentanil; Propofol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment