Original contribution
Hemodynamics and emergence profile of remifentanil versus fentanyl prospectively compared in a large population of surgical patients

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Abstract

Study Objective: To compare the responses to, and hemodynamics associated with surgical stress, recovery profiles, and anesthesiologists’ satisfaction following balanced general anesthesia using either remifentanil or fentanyl in a large-scale population.

Design: Prospective, 1:1 single blind, randomized, controlled effectiveness study in which patients received either remifentanil or fentanyl in combination with a hypnotic-based anesthesia regimen of either isoflurane or propofol.

Setting: Multicenter study including 156 hospitals and ambulatory surgery facilities.

Patients: 2,438 patients (1,496 outpatients and 942 inpatients), 18 years of age or older, scheduled for elective surgeries under general endotracheal anesthesia, with an expected duration of unconsciousness ≥30 minutes.

Interventions: Patients were randomized to receive either intravenous (IV) remifentanil (0.5 μg/kg/min for induction and intubation, with the infusion rate decreased to 0.25 μg/kg/min after intubation) or IV fentanyl (administered according to anesthesiologists’ usual practice) as the opioid during surgery. Concomitant hypnotic drugs were either propofol and/or isoflurane (with or without nitrous oxide) titrated according to protocol. Transition analgesia with either morphine or fentanyl was given to the remifentanil patients and, at the anesthesiologists’ discretion, in the fentanyl patients.

Measurements: Vital signs, adverse events, and emergence profiles were assessed and recorded. Recovery profile was assessed by recording time spent in the postanesthesia care unit and step-down recovery unit, number and timing of adverse events, timing and dosage of rescue medications, and time to eligibility for discharge (to home or to hospital room). Anesthesiologists’ satisfaction with the anesthetic regimen was assessed at the end of surgery.

Main Results: Remifentanil-treated patients exhibited lower systolic and diastolic blood pressures (by 10–15 mmHg) and lower heart rates (by 10–15 bpm) intraoperatively compared to the fentanyl-treated patients. This difference promptly disappeared on emergence. Remifentanil-treated patients responded to verbal command, left the operating room, and (for outpatients) were discharged home sooner than fentanyl-treated patients. Anesthesiologists rated the predictability of response to intraoperative titration, assessment of hemodynamic profiles, and the quality of anesthesia higher in the remifentanil-treated patients.

Conclusions: This study confirms previous observations on the hemodynamic properties associated with remifentanil and extends these to a wider context than previously reported. These characteristics provide clinicians with an alternative in opioid-based anesthesia.

Introduction

Remifentanil hydrochloride (Ultiva) is a short-acting opioid of the phenylpiperidine class. The phenylpiperidines are more potent than alkaloid opiates, provide pure mu-opioid receptor agonist effects, and find wide usage in general anesthesia and conscious sedation techniques.1, 2 Remifentanil possesses an ester bond on a side chain from the phenylpiperidine ring unlike other members of this class (e.g., alfentanil, sufentanil, and fentanyl). This ester bond is readily hydrolyzed by nonspecific plasma and tissue enzymes. Remifentanil has a terminal half-life of 8 to 20 minutes,3 and a context-sensitive half-time of approximately 3 minutes.4 The principal metabolite of remifentanil is the deesterified carboxylic acid GR90291, which has no clinically observable opioid properties.5 Like other anesthetic agents, age influences pharmacokinetic-pharmacodynamic relationships for remifentanil.6, 7

Hemodynamic stability and absence of somatic responses may be achieved by inducing profound anesthetic states; however, this usually carries the penalties of slow emergence and delayed recovery. The effectiveness of intravenous opioid anesthetic regimens must, thus, be compared during both the intraoperative and recovery stages of anesthesia.8 This study was designed as a Phase IV prospective trial in a large surgical population to investigate whether the desired intraoperative characteristics of remifentanil, in comparison with fentanyl, could be obtained while achieving a fast, predictable recovery from anesthesia.

Section snippets

Ethical and regulatory considerations

This study complied with the Declaration of Helsinki (as amended) and was approved by the institutional review board of each of the participating institutions. All patients provided written informed consent.

Overview of study design

Anesthesiologists first participated in an open-label, remifentanil-based balanced infusional technique on ten patients to gain experience using the drug. In the next phase of the study, two balanced anesthetic regimens were compared using a parallel-group, 1:1 randomized, controlled

Demographics

For inpatients, the safety and intent-to-treat populations were 477 and 465 for remifentanil and fentanyl, respectively. For outpatients, the safety population was 752 and 744 for remifentanil- and fentanyl-based regimens, respectively. For one outpatient, the surgical procedure was emergently canceled, and the intent-to-treat populations were 751 and 744 for remifentanil and fentanyl, respectively. Demographic characteristics of these populations were comparable between treatment groups,

Discussion

We compared hemodynamics and recovery outcomes observed during and after remifentanil- versus fentanyl-based balanced anesthesia regimens in a large-scale, multicenter, randomized, single-blind study. This is the largest study to date (2,438 patients) comparing intraoperative and recovery profiles of two phenylpiperidine opioids. Inpatients and outpatients were studied separately because of predictable demographic differences in age, ASA status, and type and duration of surgery. Statistically

Acknowledgements

We thank the investigators, other advisory panel members (Kenneth Tuman, Michael Roizen, Peter Glass), Deborah Thompson (Project Leader), study site coordinators, and patients who took part in this study.

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This study was sponsored by GlaxoWellcome Inc., Research Triangle Park, NC, USA, under protocol number USAA4001.

Professor of Clinical Anesthesiology, Department of Anesthesiology, SUNY Health Science Center at Brooklyn

Head, Clinical Development, Neurosciences Medical Affairs, GlaxoSmithKline, Triangle Park, NC

Professor of Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, NC

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Associate Professor of Anesthesiology, Joint Appointments in Medicine, Biomedical Information Sciences and Health Policy & Management, Clinical Director of Operating Rooms, Johns Hopkins Medicine

Senior Analyst, Principal Health Outcomes Scientist, GlaxoSmithKline

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