Drugs

Battershill, Anna J.; Keating, Gillian M.

doi: 10.2165/00003495-200666030-00013pmid: 16526829

SummaryAbstractRemifentanil (Ultiva™), a 4-anilidopiperidine derivative of fentanyl, is an ultra-short-acting μ-opioid receptor agonist indicated to provide analgesia and sedation in mechanically ventilated intensive care unit (ICU) patients.Analgesia-based sedation with remifentanil is a useful option for mechanically ventilated patients in the ICU setting. Its unique properties (e.g. organ-independent metabolism, lack of accumulation, rapid offset of action) set it apart from other opioid agents. Remifentanil is at least as effective as comparator opioids such as fentanyl, morphine and sufentanil in providing pain relief and sedation in mechanically ventilated ICU patients. Moreover, it allows fast and predictable extubation, as well as being associated with a shorter duration of mechanical ventilation and quicker ICU discharge than comparators in some studies. In addition, remifentanil is generally well tolerated in this patient population. Thus, remifentanil is a welcome addition to the currently available pharmacological agents employed in the management of mechanically ventilated ICU patients.Pharmacological PropertiesRemifentanil is a 4-anilidopiperidine derivative of fentanyl containing an ester linkage to propanoic acid. It is ultra-short acting and displays analgesic effects, consistent with its agonist activity at the μ-receptor. The primary metabolite, remifentanil acid, has negligible activity compared with remifentanil. Remifentanil has a rapid onset of action (≈1 minute) and a rapid offset of action following discontinuation (≈3–10 minutes). The time to offset of action was not prolonged to a clinically significant extent by renal impairment or prolonged infusion in post-surgical or medical ICU patients who received remifentanil for up to 72 hours. In mechanically ventilated ICU patients, the median time to offset of action was significantly shorter with remifentanil than with morphine or fentanyl after 10 days’ treatment.The effect of remifentanil on haemodynamics is typical of opioids (e.g. decreased blood pressure and heart rate). In ICU patients, remifentanil was generally associated with an acceptable degree of haemodynamic stability. There were no significant differences between remifentanil, fentanyl and morphine recipients in mean intracranial pressure (ICP) or cerebral perfusion pressure in mechanically ventilated ICU patients with acute brain injury or who had undergone neurosurgery. However, compared with baseline, ICP was significantly increased and cerebral perfusion pressure was significantly reduced with remifentanil in mechanically ventilated patients with severe traumatic brain injury in another study.Remifentanil is rapidly distributed throughout the body and demonstrates linear, dose-dependent, multicompartmental pharmacokinetics. The drug undergoes widespread extravascular metabolism and is rapidly metabolised via extrahepatic, nonspecific blood and tissue esterases to remifentanil acid. The pharmacokinetics of remifentanil were not altered to a clinically significant extent in ICU patients with moderate to severe renal impairment who received the drug for up to 72 hours, compared with ICU patients with normal renal function or mild renal impairment. The pharmacokinetics of remifentanil were also not altered to a clinically significant extent in patients with severe chronic liver disease. Remifentanil has a context-sensitive half-time of ≈3–4 minutes, irrespective of the duration of infusion. Age-related changes in clearance and volume of distribution occurred in paediatric patients receiving remifentanil.Therapeutic EfficacyA number of well designed trials have compared the use of analgesia-based sedation with remifentanil with that of morphine, fentanyl or sufentanil in post-surgical, trauma and/or medical patients (n ≥ 20) who were being mechanically ventilated in an ICU setting.Remifentanil provided effective analgesia-based sedation in mechanically ventilated patients in the ICU setting. Optimal sedation was achieved for ≥78% of the time with remifentanil. Moreover, with remifentanil, the duration of optimal sedation and the percentage of hours during which patients had no or mild pain was generally similar to that with fentanyl or morphine. In addition, compared with remifentanil, the need for additional sedation generally appeared greater with fentanyl and morphine regimens, but not with sufentanil regimens.Remifentanil was at least as effective as fentanyl, morphine and sufentanil in terms of recovery parameters. In some studies, including a study examining longer-term mechanical ventilation, remifentanil was associated with a significantly shorter duration of mechanical ventilation than fentanyl or morphine. In addition, remifentanil was associated with a significantly shorter extubation time than fentanyl, morphine or sufentanil and a shorter time to ICU discharge than fentanyl or morphine in some studies. Two studies noted an absence of tolerance to remifentanil, although tolerance was seen in 29% of remifentanil recipients in another study. A remifentanil-based regimen may also be associated with savings in staff costs, according to the results of a prospective cost-consequence analysis.Remifentanil was associated with rapid and predictable emergence from sedation in mechanically ventilated ICU patients with acute brain injury or who had undergone neurosurgery in a randomised, nonblind study. Significantly less between-patient variability in the time to neurological assessment occurred in patients receiving analgesia-based sedation with remifentanil than in those receiving hypnotic-based sedation incorporating fentanyl or morphine. Remifentanil patients requiring mechanical ventilation were extubated significantly earlier than patients receiving the morphine-based regimen. The extubation time and time until ICU discharge were also significantly shorter with remifentanil plus propofol than with fentanyl plus midazolam in mechanically ventilated ICU patients who had undergone supratentorial brain surgery in a retrospective study.Remifentanil provided similar analgesia-based sedation to fentanyl in paediatric patients aged 3–16 years who were being mechanically ventilated following orthopaedic spinal surgery. Remifentanil also demonstrated efficacy in mechanically ventilated newborns.Remifentanil provided adequate analgesia in ICU patients with severe burns during dressing changes, and an intravenous infusion of remifentanil effectively reduced stress during endotracheal suctioning in mechanically ventilated post-surgical ICU patients sedated with sufentanil.TolerabilityRemifentanil was generally well tolerated in ICU patients requiring mechanical ventilation. The most commonly occurring adverse events in remifentanil recipients relate to its μ-opioid agonist properties (e.g. bradycardia, hypotension).The tolerability of remifentanil was generally similar to that of fentanyl or morphine in ICU patients requiring short-term mechanical ventilation for up to ≈3 days. In terms of the proportion of patients experiencing drug-related adverse effects, there was no significant difference between remifentanil and morphine recipients (22% vs 16%), or between remifentanil and fentanyl recipients (23% vs 17%). Moreover, there was no significant difference between remifentanil and fentanyl recipients in the incidence of hypotension, nausea, fever or vomiting.In critically ill patients mechanically ventilated for up to 10 days, drug-related adverse events occurred in 11% of recipients and in 8% of patients receiving a comparator regimen (midazolam with fentanyl or morphine). The most commonly occurring adverse events in remifentanil recipients (occurring in ≥5% of patients, not necessarily drug related) included hypotension, atrial fibrillation and vomiting. Muscle rigidity did not occur in either treatment group.Remifentanil was also generally well tolerated in mechanically ventilated paediatric patients in the ICU setting.