Interactions between Midazolam and Remifentanil during Monitored Anesthesia Care
Authors: Avramov Michail N. , Smith Ian , White Paul F. 
Published: November 2003

Background
Remifentanil, an ultra-short-acting opioid analgesic, may be useful as an intravenous adjuvant to local anesthesia for treating patient discomfort and pain during monitored anesthesia care (MAC). However, the remifentanil dose requirements, interactions with other commonly used sedative drugs (such as midazolam), and recovery characteristics after ambulatory procedures have not been determined. Therefore, this study was designed to evaluate the safety and efficacy of remifentanil alone and in combination with different doses of midazolam during MAC.

Methods
Eighty-one healthy consenting women scheduled for elective breast biopsy procedures were randomly assigned to one of four treatment groups according to an institutional review board-approved, double-blind, placebo-controlled protocol. The study medication (containing either saline or 2 mg, 4 mg, or 8 mg of midazolam) was administered intravenously 5 min before starting an infusion of remifentanil at 0.1 microgram.kg-1.min-1. The remifentanil infusion was subsequently adjusted in 0.025- and 0.05-microgram.kg-1.min-1 increments to maintain patient comfort and adequate ventilation during the operation. The level of sedation was assessed at 1- to 10-min intervals during the procedure using the inverted observer's assessment of alertness/sedation (OAA/S) scale, with a score of 1 = awake, alert to 5 = asleep, unarousable. Discomfort and pain were assessed using numerical rating scales. Hemoglobin oxygen saturation, respiratory rate, blood pressure (systolic, diastolic, mean), and heart rate were monitored at 1- to 5-min intervals. Intraoperative amnesia was assessed by asking patients to recall a picture shown 5 min after the study medication was administered. Recovery was evaluated using the Aldrete score and the times to "home readiness" and actual discharge. Side effects and patient satisfaction were assessed in a follow-up telephone interview on the first postoperative day.

Results
Midazolam produced dose-dependent increases in the median level of sedation. Remifentanil produced a greater reduction in respiratory rate in the 4-mg and 8-mg midazolam groups. However, there were no significant differences in the hemodynamic variables or discharge times. Patients with OAA/S scores of 1 to 3 ("light" sedation) 5 min after the study medication experienced a greater incidence of intraoperative pruritus and postoperative nausea and vomiting (PONV) compared with those with OAA/S scores of 4 to 5 ("deep" sedation). Discharge times were prolonged for patients in the light sedation group in whom PONV developed.

Conclusions
Use of remifentanil alone for MAC did not provide optimal sedation during local anesthesia. However, 0.05 to 0.1 microgram.kg-1.min-1 remifentanil in combination with 2 mg midazolam given intravenously, provided effective sedation and analgesia during MAC in healthy patients classified as American Society of Anesthesiologists status 1 to 2. Midazolam also produced dose-dependent potentiation of remifentanil's depressant effect on respiratory rate. In outpatients receiving a combination of midazolam and remifentanil during local anesthesia, the level of sedation appears to influence the incidence of both intraoperative pruritus and PONV.