Remifentanil

Remifentanil is an ultra-short-acting synthetic mu opioid agonist broken down by non-specific blood and tissue esterases, so its effect ends within minutes of stopping the infusion regardless of how long it ran. It gives precise, rapidly titratable analgesia during anaesthesia and intensive care. Because it leaves no residual analgesia, longer-acting analgesia must be started before it is stopped. It causes dose-related respiratory depression, bradycardia, hypotension and muscle rigidity.

Class. Opioid analgesic (phenylpiperidine, mu receptor agonist).

Mechanism. Agonist at mu opioid receptors, reducing nociceptive transmission and producing analgesia, respiratory depression and sedation. Potency is similar to fentanyl.

Pharmacokinetics. Onset within 1 minute; peak effect 1 to 3 minutes. Effect-site equilibration half-time about 1.3 minutes. Context-sensitive half-time about 3 minutes irrespective of infusion duration. Terminal half-life 10 to 20 minutes. Protein binding about 70%. Volume of distribution about 0.3 L/kg. Clearance about 40 mL/kg/minute, unaffected by liver or kidney failure and by plasma cholinesterase deficiency. The main metabolite, remifentanil acid, is about 4600 times less potent and is excreted by the kidney.

Indications are analgesia during induction and maintenance of general anaesthesia (including intubation without a muscle relaxant), analgesia and sedation of ventilated patients in intensive care, and specialist use in awake procedures and in labour.

Adults, anaesthesia

• Induction: infusion 0.5 to 1 microgram/kg/minute, with an optional bolus of 1 microgram/kg given over at least 30 seconds.
• Maintenance with nitrous oxide (66%): 0.4 microgram/kg/minute (range 0.025 to 2 micrograms/kg/minute). With a volatile agent or propofol the usual range is 0.05 to 2 micrograms/kg/minute, and the requirement of both drugs falls.
• Supplementary boluses: 0.5 to 1 microgram/kg every 2 to 5 minutes for light anaesthesia.
• Target-controlled infusion with a validated model: effect-site target 4 to 8 nanograms/mL for intubation, 2 to 5 nanograms/mL for maintenance, adjusted to response.
• Older adults: halve the starting dose and titrate. Obesity: dose by ideal body weight.

Adults, intensive care

• Start 0.1 to 0.15 micrograms/kg/minute and titrate by 0.025 micrograms/kg/minute steps every 5 minutes, usually within 0.006 to 0.74 micrograms/kg/minute. Give no bolus.
• Add a sedative for adequate sedation. Limit use to about 3 days in most labels.

Postoperative analgesia. Give a longer-acting analgesic (an opioid, paracetamol or a regional block) 30 to 60 minutes before stopping, because analgesia ends within 5 to 10 minutes. Give the first dose of the opioid while the infusion is still running.

Children

• Ages 1 to 12 years: bolus 1 microgram/kg then maintenance 0.05 to 1.3 micrograms/kg/minute during anaesthesia.
• Neonates and infants under 1 year: maintenance 0.4 to 1 microgram/kg/minute with a volatile agent or nitrous oxide.
• Intensive care sedation in children and neonates is off-label and specialist.

Contraindications. Hypersensitivity to remifentanil or other fentanyl-class opioids; intrathecal or epidural injection (the glycine in the vial is neurotoxic); use as the sole agent for induction; unmonitored use or use outside a setting able to ventilate the patient.

Boxed-warning-level risks. Respiratory depression and apnoea; profound bradycardia, hypotension and asystole with rapid bolus; muscle rigidity of the chest wall; dependence and rapid tolerance with hyperalgesia after high-dose infusion; risk with other central nervous system depressants.

Adverse effects. Common: nausea, vomiting, hypotension, bradycardia, shivering, pruritus. Serious: apnoea, chest wall rigidity, asystole, acute opioid tolerance and postoperative hyperalgesia, severe postoperative pain after abrupt cessation, withdrawal after prolonged intensive care use, serotonin syndrome with serotonergic drugs.

Interactions. Propofol, volatile agents, benzodiazepines, alpha-2 agonists and nitrous oxide lower the requirement of each drug by up to 50% or more and add to hypotension. Beta blockers and calcium channel blockers add bradycardia. Neuromuscular blockers mask rigidity. Serotonergic drugs (monoamine oxidase inhibitors, linezolid) may precipitate serotonin syndrome.

Common prescribing errors. Stopping the infusion without prior analgesia; flushing residual drug from a shared line into the patient, giving an unplanned bolus; confusing micrograms/kg/minute with micrograms/kg/hour; reconstituting at a wrong concentration; infusing through a line without a one-way valve; giving a large bolus quickly and causing apnoea or asystole; use in spontaneously breathing patients without monitoring.

Special groups

• Pregnancy: crosses the placenta but is cleared rapidly in the foetus and neonate; used at caesarean section with respiratory depression risk for the newborn; labour use is specialist and off-label, with one-to-one care.
• Breastfeeding: compatible after the infusion stops because of rapid clearance.
• Older adults: more sensitive; reduce the starting dose by 50%.
• Kidney impairment: no adjustment; metabolite is inactive.
• Liver impairment: no adjustment; reduced sensitivity to esterase deficiency.
• Regional: availability and cost limit use; where it is available, infusion pumps with accurate low-rate delivery and a labelled dilution (for example 50 micrograms/mL) reduce errors.

Formulations. Powder for reconstitution in 1 mg, 2 mg and 5 mg vials.

Administration. Reconstitute with 1 mL of diluent for each 1 mg to give 1 mg/mL, then dilute to 20 to 250 micrograms/mL in 0.9% sodium chloride or 5% glucose (50 micrograms/mL is usual). Use within 24 hours of reconstitution. Give through a dedicated line, or a line with a one-way valve close to the cannula, and do not flush the line into the patient after stopping.

Baseline. Airway assessment, heart rate, blood pressure, current opioids, serotonergic medicines, weight (ideal body weight in obesity).

Monitoring. Continuous electrocardiogram, oxygen saturation, capnography and blood pressure. Respiratory rate in spontaneously breathing patients. In intensive care, daily review of the need for infusion and sedation scoring.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Reduce the rate for hypotension, bradycardia or heart rate under 50 beats/minute. In spontaneously breathing patients stop the infusion for respiratory rate under 10 breaths/minute, oxygen saturation under 94% or loss of responsiveness. After use for more than 1 week, reduce the rate by 10 to 25% every few days to prevent withdrawal.

Referral and escalation. Bradycardia needs glycopyrronium 0.2 mg or atropine 0.5 to 1 mg intravenously. Hypotension needs fluids and a vasopressor such as ephedrine 6 mg or phenylephrine 50 to 100 micrograms. Chest wall rigidity needs a neuromuscular blocker and ventilation. Persistent apnoea after stopping needs ventilation and naloxone 40 micrograms increments intravenously every 2 minutes. Asystole needs advanced life support.