Remifentanil is a new potent μ-agonist that retains all the pharmacodynamic characteristics of its class (analgesia, haemodynamic stability, respiratory depression, muscle rigidity, nausea and vomiting, pruritus, etc.) but with a unique pharmacokinetic profile due to rapid metabolism by non-specific tissue esterases [1-3]. Its potency is of the same order of magnitude as that of fentanyl, and it is about 20 times more potent than alfentanil [2,4,5]. Its onset of action is similar to that of alfentanil, which reflects similar equilibration times between blood and effect site concentrations, but its duration of effect is much shorter , and its measured context-sensitive half-time averages 3 min after an infusion of 3 h . Soon to be released in everyday practice, its clinical profile can now be outlined, but only widespread use will accurately define its main indications and optimal dosage.
Remifentanil use during general anaesthesia
Clinical reports of the use of remifentanil during general anaesthesia remain sparse, but it is possible to extrapolate from its pharmacodynamic profile that the best situations to choose it are:
- when a high opioid concentration is indicated but nevertheless a rapid recovery is required;
- when the intra-operative level of stimulation is very high or very variable;
- when the benefit from the synergy between hypnotics and opioids is sought, and there is no need for postoperative analgesia.
Any dosage of remifentanil may be used during surgery without undue lengthening of emergence times . In clinical practice, high doses of remifentanil may nevertheless have drawbacks: remifentanil reduces the MAC of isoflurane  and the EC50 of propofol, and the hypnotics may be used at lower concentrations or infusion rates than when other opioids are considered , but the reduction in the amount of hypnotics administered increases the risk of awareness during anaesthesia, specifically if there is any interruption in the infusion of remifentanil . The incidence of postoperative nausea and vomiting is high in opioid based anaesthetic techniques and remifentanil is no exception . Therefore, the currently recommended dosage includes a bolus dose of 1 mg kg−1 remifentanil followed by an infusion of 0.5 mg kg−1 min−1 to be reduced after 5 min to 0.25 mg kg−1 min−1, associated with moderate or low amounts of hypnotics (e.g. propofol 75 - 100 mg kg−1 h−1 or 2 - 3 μg ml−1 with a target-controlled infusion [TCI]). This remifentanil dosage can be adapted to the patient's needs with no risk of delayed recovery . If a TCI is to be used, the target concentrations reflect the potency of remifentanil, similar to that of fentanyl. This mode of administration suppresses any temptation to administer a manual bolus dose during remifentanil infusion.
Remifentanil and cardiac surgery
Administration of high doses of opioids is the best way to blunt the stress response, which explains their wide use in cardiac-compromised patients. Nevertheless, such administration of currently available opioids leads to delayed recovery and extubation, and other possibly less optimal but cost-saving anaesthetic regimens have recently been proposed . Remifentanil may combine the requirement for intra-operative control of the stress response and rapid recovery. A first step towards the use of remifentanil in cardiac surgery was to assess if remifentanil retained its unique pharmacokinetic profile during cardiopulmonary bypass and hypothermia. In fact, hypothermia reduced the clearance of remifentanil and doubled its elimination half-life , but this can induce no postoperative remifentanil accumulation. Doses of remifentanil up to 30 mg kg−1 were unable to elicit histamine release during balanced anaesthesia , and the haemodynamic profile of remifentanil is therefore the same as that of the other piperidine derivatives. When compared to a currently advocated anaesthetic regimen for open heart surgery allowing early extubation and discharge from the ICU, remifentanil allowed a better intra-operative control of stress response and faster extubation and discharge . These results, concerning only a small number of patients, remain to be confirmed, as assessed by a subsequent comment published in the same journal . In these studies, the dosing scheme for remifentanil was 1 - 2 mg kg−1 min−1 in a total intravenous technique with propofol and pancuronium. Like other potent opioids, remifentanil may induce muscle rigidity when a large dose is infused rapidly. During the early postoperative phase, the patients received only remifentanil, 1 mg kg−1 min−1, followed by morphine after extubation. The very swift termination of remifentanil action calls for modification of the usual anaesthetic management of cardiac cases to ensure uneventful recovery and efficient postoperative analgesia.
Remifentanil and neurosurgery
The effects of remifentanil on intracranial pressure and cerebral blood flow are quite similar to those of alfentanil [16,17]. During craniotomy the intensity of painful stimuli varies greatly, and a rapid and predictable emergence is warranted to assess early neurological status after surgery. Remifentanil therefore appears a useful drug in this situation.
Remifentanil in special patients groups
Remifentanil metabolism is independent of hepatic and of renal function, as well as unaffected by pseudocholinesterase activity . As a consequence, the pharmacokinetics of remifentanil are not modified in patients with severe hepatic or renal dysfunction [19,20]. Remifentanil has a weakly active carboxylic acid metabolite that is mainly eliminated through the kidney . The activity of the compound is only 1/300 - 1/1000 of that of remifentanil and so it does not contribute to remifentanil analgesic effect during anaesthesia even of patients with renal failure. Subjects with severe hepatic dysfunction were more sensitive than control patients to the ventilatory depressant effect of remifentanil, but the duration of remifentanil action was not enhanced in this population .
A major concern when using remifentanil during general anaesthesia is postoperative analgesia which must be planned and initiated at or before the end of the procedure. Clinical investigations are currently lacking to help the choice of the postoperative analgesic protocol. According to the magnitude of the expected postoperative pain, administration of propacetamol, a non-steroidal antiinflammatory agent, or morphine can be considered. Another option is to continue remifentanil infusion at a lower rate (see below).
Remifentanil use during local or regional anaesthesia as part of monitored anaesthesia care
Opioids as sedative drugs may be useful to alleviate pain during block placement and to induce a feeling of well being during surgery without loss of control. Remifentanil, with its short onset and easy titration, can be specifically useful in this setting where immediate postoperative analgesia is ensured by the local anaesthetic. Remifentanil alone did not lead to optimal sedation and the association with small (2 mg) doses of midazolam at the beginning of the procedure increased the patient's comfort and provided significant intraoperative amnesia . The use of co-administered sedatives also reduced the incidence of nausea, vomiting and pruritus, which approximately 30% of the patients who did not receive midazolam experienced. Increasing the dose of midazolam increased the incidence of unwanted effects such as oversedation and respiratory depression. The best infusion rate of remifentanil in this situation was 0.1 mg kg−1 min−1 and was not significantly reduced by the administration of midazolam. This is consistent with the weak synergism between opioids and hypnotics for loss of consciousness or recovery . The best way to administer remifentanil during monitored sedation remains to be investigated, considering the advantages of patient-controlled sedation. Administration of remifentanil boluses may lead to significant respiratory depression and even apnoea . The patient should therefore rather have a control over the remifentanil infusion rate, or even over a target concentration during a TCI.
Remifentanil: a suitable spinal analgesic?
Spinal administration of remifentanil has been compared to that of alfentanil and morphine in rats . Remifentanil elicited a rapid onset of action similar to that of alfentanil. Despite lipid solubility leading to a rapid systemic absorption, remifentanil kept a significant spinal therapeutic ratio, possibly due to the rapid plasma inactivation of the redistributed fraction. Nevertheless, when infused at analgesic effective doses supraspinal redistribution led to measurable systemic effects . These initial animal studies also demonstrated that the current glycine vehicle of remifentanil could be associated with motor weakness after spinal administration .
Use of remifentanil for postoperative analgesia
One of the major problems of remifentanil use is the planning of postoperative analgesia. An elegant solution is to reduce remifentanil infusion at the end of the procedure to allow spontaneous breathing and extubation while maintaining adequate analgesia. After surgical procedures leading to significant postoperative pain, an infusion rate of remifentanil between 0.05 and 0.15 mg kg−1 min−1 ensured adequate analgesia in 78% of the patients during the first hour after surgery, but some patients required doses well outside this range . Even in the carefully controlled setting of clinical investigation, 8% of the patients became apnoeic or required the administration of naloxone for severe respiratory depression. These events were usually triggered by the administration of a remifentanil bolus. Another risk is the rapid flush of an infusion line containing remifentanil. This risk can be avoided by reducing as much as possible the dead space between the remifentanil line and the patient's blood. The wide inter-individual variability of the dosages required calls for the patient to have control over remifentanil infusion rates. Boluses should be avoided in all circumstances. In the clinical setting, if remifentanil administration during surgery is not to be continued throughout all the postoperative period, early pain control with remifentanil during the transportation to the recovery ward of a conscious extubated patient may ensure the best transition to another postoperative analgesic regimen.
The pharmacodynamic profile of remifentanil in clinical practice corresponds to what was expected from this drug from the start: it is versatile, manageable, and, if used adequately, it increases safety by allowing avoidance of the risk of delayed respiratory depression. Nevertheless, current clinical studies have also confirmed that effective use of remifentanil cannot be achieved without major changes in the management of analgesia, both intra- and post-operatively, and in prescribing habits. Remifentanil has become available at a time when intravenous anaesthesia is maturing rapidly through the widespread use of TCI, and it is part of that maturation.
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Seventh International Symposium on Intravenous Anaesthesia, Lausanne, Switzerland, 2-3 May 1997
This publication is supported by grants from various pharmaceutical companies. The views in this publication are those of the authors and not necessarily those of supporting companies. Drugs and administration techniques referred to should only be used as recommended in the manufacturers' prescribing information.