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

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

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.

Study Overview

• Status: Unknown
• Conditions: Anesthesia
• Intervention / Treatment: Drug: Propofol; Drug: Remifentanil; Drug: Midazolam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jiwon An, MD; Phone Number: 82-2-2019-3520

Study Locations

• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 135-720
      • Recruiting
      • Gangnam Severance Hospital, Yonsei University College of Medicine
      • Contact: Dong Woo Han, MD, PhD; Phone Number: 82-2-2019-3520

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Group P; Induction with propofol bolus. Dose will be started at 0.5 mg/kg and will be adjusted as described in summary.	Drug: Propofol; Propofol bolus dose administration according to the predetermined dose by biased coined design up-and-down study.; Other Names: Fresofol
ACTIVE_COMPARATOR: Group PR; 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; Propofol bolus dose administration according to the predetermined dose by biased coined design up-and-down study.; Other Names: Fresofol; Drug: Remifentanil; Remifentanil 0.125 mcg/kg/min infusion for 5 min before propofol administration.; Other Names: Ultiva
ACTIVE_COMPARATOR: Group PMR; 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; Propofol bolus dose administration according to the predetermined dose by biased coined design up-and-down study.; Other Names: Fresofol; Drug: Remifentanil; Remifentanil 0.125 mcg/kg/min infusion for 5 min before propofol administration.; Other Names: Ultiva; Drug: Midazolam; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gangnam Severance Hospital
• Investigators: Study Chair: Dong Woo Han, MD,PhD, Gangnam Severance Hospital

Publications and helpful links

General Publications

• Conway DH, Hasan SK, Simpson ME. Target-controlled propofol requirements at induction of anaesthesia: effect of remifentanil and midazolam. Eur J Anaesthesiol. 2002 Aug;19(8):580-4. doi: 10.1017/s0265021502000935.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (ANTICIPATED): October 1, 2016
• Study Completion (ANTICIPATED): October 1, 2016

Study Registration Dates

• First Submitted: June 22, 2016
• First Submitted That Met QC Criteria: June 28, 2016
• First Posted (ESTIMATE): June 29, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): June 29, 2016
• Last Update Submitted That Met QC Criteria: June 28, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: midazolam; pharmacodynamics; propofol; remifentanil; combination; synergic; Loss of consciousness
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Consciousness Disorders; Unconsciousness; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Remifentanil; Midazolam; Propofol
• Other Study ID Numbers: 3-2015-0222