Remifentanil and Midazolam on Propofol for Loss of Consciousness in Elderly Patients

Study Overview
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Brief Summary
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Propofol is a well-known induction agent which can provide sound and quick hypnosis with anti-emetic effects. However, dose dependent hypotension or bradycardia have reported while using this agent. Propofol in combination with remifentanil or midazolam can result in synergistic or additive effect in elderly patients. There are not many studies which provide minimum dose of propofol to induce hypnosis in combination with these agents and advantage of the combination. The elderly patients (over 65 years old) who are scheduled to undergo general anesthesia are enrolled in this study. 120 patients will be randomly allocated to 3 groups(P, PR, PMR). Sample size have been decided due to the previous studies which have mentioned 40 participants as a adequate sample size for this biased coin design - up and down study. After receiving informed consent, patients will be participated in this study. No premedication will be given to the patients before induction. The patients in group P will receive general anesthesia only with propofol and group PR and PMR will receive 0.125 mcg/kg/min remifentanil infusion for 5 min prior to propofol administration. The patients in group PMR will receive 0.015 mg/kg bolus dose of midazolam 1 min after the start of the remifentanil infusion. Initial propofol dose will be 0.5 mg/kg in each group and the dose will be changed by the result of prior study participant. 'Success' of this study will be defined as loss of both verbal response and eyelash reflex in 3 min after propofol administration. When 'success', the next patient will receive the same dose(in 18/19 probability) or 0.125 mg/kg lower dose(in 1/19 probability) of propofol. When 'failure', the next patient will receive 0.125 mg/kg higher dose of propofol at induction period.

Detailed Description
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Propofol is a well-known induction agent which can provide sound and quick hypnosis with anti-emetic effects. However, dose dependent hypotension or bradycardia have reported while using this agent. Propofol in combination with remifentanil or midazolam can result in synergistic or additive effect in elderly patients. There are not many studies which provide minimum dose of propofol to induce hypnosis in combination with these agents and advantage of the combination. The elderly patients (over 65 years old) who are scheduled to undergo general anesthesia are enrolled in this study. 120 patients will be randomly allocated to 3 groups(P, PR, PMR). Sample size have been decided due to the previous studies which have mentioned 40 participants as a adequate sample size for this biased coin design - up and down study. After receiving informed consent, patients will be participated in this study. No premedication will be given to the patients before induction. The patients in group P will receive general anesthesia only with propofol and group PR and PMR will receive 0.125 mcg/kg/min remifentanil infusion for 5 min prior to propofol administration. The patients in group PMR will receive 0.015 mg/kg bolus dose of midazolam 1 min after the start of the remifentanil infusion. Initial propofol dose will be 0.5 mg/kg in each group and the dose will be changed by the result of prior study participant. 'Success' of this study will be defined as loss of both verbal response and eyelash reflex in 3 min after propofol administration. When 'success', the next patient will receive the same dose(in 18/19 probability) or 0.125 mg/kg lower dose(in 1/19 probability) of propofol. When 'failure', the next patient will receive 0.125 mg/kg higher dose of propofol at induction period.

Official Title
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The Effect of Remifentanil and Midazolam on Propofol for Loss of Consciousness During Induction of Anesthesia in Elderly Patients

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: Propofol
* Drug: Remifentanil
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The elderly patients (over 65 years old) who are scheduled to undergo general anesthesia. Exclusion Criteria: ASA class (American Society of Anesthesiologist physical status classification) IV or higher Patients with history of allergy or side effects on propofol, remifentanil, midazolam BMI (body mass index) less than 20 or higher than 30 Patients taking sedatives or hypnotic agents.

Ages Eligible for Study
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Minimum Age: 65 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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group P<br>Induction with propofol bolus. Dose will be started at 0.5 mg/kg and will be adjusted as described in summary. | Drug: Propofol<br>* Propofol bolus dose administration according to the predetermined dose by biased coined design up-and-down study.<br>* Other names: Fresofol;|
| Active Comparator: Group PR<br>Induction with propofol and remifentanil. Remifentanil infusion 0.125 mcg/kg/min for 5 min followed by propofol bolus Propofol dose will be started at 0.5 mg/kg and will be adjusted as described in summary. | Drug: Propofol<br>* Propofol bolus dose administration according to the predetermined dose by biased coined design up-and-down study.<br>* Other names: Fresofol;Drug: Remifentanil<br>* Remifentanil 0.125 mcg/kg/min infusion for 5 min before propofol administration.<br>* Other names: Ultiva;|
| Active Comparator: Group PMR<br>Induction with propofol, midazolam and remifentanil. Remifentanil infusion 0.125 mcg/kg/min for 5 min followed by midazolam 0.015 mg/kg bolus 1 min after remifentanil infusion start and propofol bolus administration. Propofol dose will be started at 0.5 mg/kg and will be adjusted as described in summary. | Drug: Propofol<br>* Propofol bolus dose administration according to the predetermined dose by biased coined design up-and-down study.<br>* Other names: Fresofol;Drug: Remifentanil<br>* Remifentanil 0.125 mcg/kg/min infusion for 5 min before propofol administration.<br>* Other names: Ultiva;Drug: Midazolam<br>* Remifentanil 0.125 mcg/kg/min infusion for 5 min before propofol administration followed by midazolam 0.015 mg/kg administration 1 min after remifentanil infusion start.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loss of verbal response and eyelash reflex | Checking verbal response by verbal stimulation (response or no response). | 3 minutes after propofol administration | 
| Loss of eyelash reflex | Checking reflex by palpation of the levator palpebrae (reflex or no reflex). | 3 minutes after propofol administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean blood pressure | To compare differences among groups in mean blood pressure change (mmHg) | baseline, propofol administration time (Just after finishing monitoring on the patient in P group, 5 minutes after remifentanil infusion start in PR and PMR group), 1 minute, 2 minutes and 3 minutes after propofol administration | 
| Heart rate | To compare differences among groups in heart rate change (mmHg) | baseline, propofol administration time (Just after finishing monitoring on the patient in P group, 5 minutes after remifentanil infusion start in PR and PMR group), 1 minute, 2 minutes and 3 minutes after propofol administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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propofol, midazolam, remifentanil, combination, synergic, pharmacodynamics, Loss of consciousness