MANUAL INFUSION SCHEMES FOR INTRAVENOUS ANESTHETICS

The following infusion schemes are developed from integrated pharmacokinetic-pharmacodynamic models. However, it is the patient's response, demonstrating adequate or inadequate anesthesia, that ultimately determines the rate of drug administration. Individuals vary markedly in their response to a given drug dose or concentration, and it is therefore essential to titrate

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Figure 12-21 Simulation of the interaction of propofol and remifentanil in preventing a somatic response at skin incision and time to recovery. Note that with remifentanil, the optimal combination is a propofol concentration of 2.5 µg/mL and a remifentanil concentration of 5 to 7 ng/mL and that increasing the duration of the infusion has minimal impact on recovery time if the optimal dose of remifentanil is not used. However, if the propofol dose is increased, recovery is prolonged. (Adapted from Vuyk J, Mertens MJ, Olofsen E, et al: Propofol anesthesia and rational opioid selection: Determination of optimal EC50-EC95 propofolopioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology 87:1549–1562, 1997.)

If the infusion rate proves to be insufficient to maintain adequate anesthesia, a further loading (bolus) dose and an increase in infusion are required to rapidly raise the plasma (biophase) drug concentration. Various interventions also require greater drug concentrations, usually for brief periods (e.g., laryngoscopy, endotracheal intubation, skin incision) (see Fig. 12-3 ). Therefore, the infusion scheme should be tailored to provide peak concentrations during these brief periods of intense stimulation. An adequate drug level for endotracheal intubation is

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Opioids (see Chapter 11 )

Alfentanil

As shown by the work of Ausems and associates,^[22] the highest alfentanil concentrations (in combination with 70% nitrous oxide) are required for endotracheal intubation. The concentration of alfentanil required for skin closure is less than that required for skin incision or spontaneous ventilation, which allows the opioid to be gradually titrated downward toward the end of the procedure.

Several schemes have been advocated for the infusion of alfentanil when it is used as part of a nitrous-narcotic technique.^{[88] [89] [90]} Most schemes vary in the sequence of the initial loading dose, although most provide 100 µg/kg within the first 10 minutes. Thus, the loading dose may be given as an initial rapid infusion of 50 µg/kg/min over a period of 2 minutes or two 50-µg/kg doses given before endotracheal intubation and skin incision or as a slower infusion of 10 µg/kg/min over a 10-minute period. The initial loading dose is followed by an infusion of 0.5 to 2 µg/kg/min. If the plasma concentration needs to be raised, an incremental bolus of 7 to 15 µg/kg with a 0.5-to 1-µg/kg/min increase in the infusion rate is usually successful. For the aforementioned infusion scheme, alfentanil is usually combined with 66% nitrous oxide. If a hypnotic is used with alfentanil to induce anesthesia, the dose of the hypnotic can usually be markedly reduced. Alfentanil can be infused with nitrous oxide or combined with a hypnotic for a total intravenous technique. If combined with midazolam (loading dose, 0.05 to 0.2 mg/kg; maintenance infusion, 0.05 to 0.15 µg/kg/min) or propofol (loading dose, 1 to 2 mg/kg; maintenance infusion, 50 to 150 µg/kg/min), the loading dose and infusion rate of alfentanil can be reduced to 10 to 50 µg/kg followed by 0.5 to 1 µg/kg/min. If given with a potent inhaled anesthetic at 0.3 to 0.5 MAC, both the loading dose and the infusion rate can be reduced to approximately 30% to 50% of that used with nitrous oxide alone. When alfentanil is combined with a volatile anesthetic or forms part of a total intravenous anesthetic (TIVA) technique, alfentanil is dosed to achieve plasma concentrations of 75 to 150 ng/mL. When these doses are used, the infusion of alfentanil should be discontinued approximately 10 to 20 minutes before the expected end of surgery.

For cardiac anesthesia, in the absence of adjuvant anesthetic drugs, much larger infusion rates are required (also see Chapter 50 ). An initial infusion of 40 µg/kg/min to loss of consciousness is followed by 10 µg/kg/min until cooling. On patient rewarming, the infusion rate can be restarted at 2.5 µg/kg/min. If inadequate anesthesia occurs, a bolus of 30 µg/kg usually ablates a response. Alfentanil has also been used for sedation in intensive care units. An initial loading dose of 25 µg/kg is followed by 0.25 to 0.5 µg/kg/min for 20 minutes and then titrated according to patient needs (0.1 to 2.0 µg/kg/min). A bolus of 3 µg/kg can be given when further supplementation is needed. In general, doses of alfentanil, as listed earlier, should be reduced in elderly or debilitated patients.

Fentanyl

Infusion of fentanyl has classically been used for cardiac surgery. Again, various schemes have been advocated for the loading dose and vary from a bolus of 50 µg/kg to a rapid infusion of 4 to 5 µg/kg/min for 5 minutes or 2 to 3 µg/kg/min for 10 minutes,^{[89] [90]} followed by continuous infusion of 0.1 to 1.0 µg/kg/min. These infusion schemes are designed to obtain a plasma fentanyl concentration of 20 to 40 ng/mL. Such a high dose of fentanyl has not demonstrated any advantage over infusion schemes that provide fentanyl concentrations of 5 to 10 ng/mL and are combined with a low-dose volatile anesthetic or propofol. This approach also facilitates fast tracking of cardiac patients. An initial loading dose of 10 to 20 µg/kg is followed by an infusion of 0.05 to 0.1 µg/kg/min. For non-cardiac surgery in which a nitrous-narcotic technique is used, the loading dose can be reduced to 5 to 15 µg/kg, followed by continuous infusion of 0.03 to 0.1 µg/kg/min

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Analgesic concentrations of fentanyl are obtained at a plasma concentration of 1 to 2 ng/mL.^[57] This concentration is optimal when combined with an intravenous hypnotic or potent inhaled agent or postoperatively for analgesia and is obtained after a loading dose of 1.5 to 3 µg/kg is administered, followed by continuous infusion of 0.01 to 0.04 µg/kg/min.

Sufentanil

Sufentanil has been successfully administered by infusion during cardiac anesthesia.^{[89] [90]} For use in cardiac surgery, an initial loading dose of 15 µg/kg followed by an infusion of 0.75 µg/kg/min is administered. When combined with midazolam (midazolam loading dose, 100 µg/kg; maintenance infusion, 1.0 to 2.5 µg/kg/min), the sufentanil dose is reduced to 2 µg/kg/min for 5 minutes, followed by 0.010 to 0.025 µg/kg/min thereafter. Even smaller doses of midazolam and sufentanil may be adequate for cardiac surgery. Very little has been published on the plasma concentrations or infusion rates of sufentanil required for noncardiac surgery. Several studies have established that in the concentration domain, sufentanil is approximately 10 times more potent than fentanyl. Thus, for noncardiac surgery, infusion rates are based on achieving concentrations approximately one tenth those of fentanyl. When combined with 70% nitrous oxide, a loading dose of 1 to 2 µg/kg of sufentanil followed by an infusion of 0.01 to 0.04 µg/kg/min can be used. As the analgesic component of a total intravenous technique or when combined with a volatile anesthetic, an initial loading dose of 0.2 to 0.5 µg/kg followed by an infusion of 0.005 to 0.01 µg/kg/min of sufentanil is generally appropriate to achieve sufentanil concentrations within the analgesic range of 0.1 to 0.3 ng/mL.

Remifentanil

Remifentanil is the newest μ-agonist available for administration as an analgesic during surgery. Because of its metabolism by general body esterases, the drug is best administered as an infusion. In addition, as a result of this unique metabolism, the decrease in concentration and dissipation of the opioid effect are very rapid after termination of its administration. This property enables the clinician to administer remifentanil at relatively higher analgesic concentrations than is possible with other opioids without the likelihood of prolonged respiratory depression. An initial loading infusion of 0.5 to 1 µg/kg/min is usually administered. This infusion dosage should be reduced by about 50% in the elderly. Moreover, the time to peak effect in the elderly is about 50% longer than in younger patients. Because offset of the drug effect is so rapid, to ablate the response to endotracheal intubation, the infusion should be maintained at 0.1 to 0.3 µg/kg/min until endotracheal intubation has been completed. When it is used in combination with a volatile anesthetic or propofol for noncardiac surgery, the infusion rate can then be reduced to 0.05 to 0.2 µg/kg/min. When it is used as a nitrous-narcotic technique, an infusion rate of 0.1 to 0.5 µg/kg/min is usually necessary. The infusion should be terminated only 5 to 10 minutes before the end of surgery (e.g., at the end of skin closure). If postoperative pain is likely to be present, it is important that the clinician initiate other forms of pain management either before or on termination of the remifentanil infusion. For cardiac surgery, infusion rates of 1 µg/kg/min have been used successfully with marked ablation of the stress response. Infusion rates of 0.5 µg/kg/min combined with low-dose propofol or a volatile anesthetic are also likely to be useful for cardiac surgery. Remifentanil, like all the other opioids, requires lower infusion rates to produce the same effect in elderly subjects.^{[46] [91]} In general, by the age of 50 years, the remifentanil infusion rate should be reduced by half of that given to a 21-year-old patient. An 80-year-old patient requires a remifentanil infusion rate that is just one third that required in a 21-year-old patient.