Anesthesiologists often consider competing interests when formulating a plan for induction of anesthesia. Of particular concern is the onset and duration of various effects for combinations of anesthetic drugs used in induction. Some questions include:
For a rapid-sequence induction, what is the optimal timing of drug administration so that peak effects occur at near the same time?
If planning to induce anesthesia in patients with known or suspected difficult manual bag-mask ventilation, what is the duration of apnea and/or ventilatory depression for a given combination of induction agents should manual ventilation become inadequate?
Following preoxygenation, what is the anticipated duration of maintaining reasonable oxygen saturations once a patient is rendered apneic?
When using a high-dose opioid technique for induction, what dose of sedative–hypnotic provides a near-equivalent effect to a conventional induction technique?
What is the role of sugammadex in a failed intubation when a nondepolarizing neuromuscular blocking agent is used?
Is it necessary to completely block the response to laryngoscopy and tracheal intubation, or is it reasonable to simply blunt it?
The aim of this chapter is to briefly explore, through simulation, the clinical implications of these questions. The simulations present predictions based on available models of anesthetic drug behavior and human physiology. As with any model-based simulation, the predictions are as good as the models used to make them. When providing a clinical interpretation of the predictions, their assumptions and limitations will be discussed.
THE IMPORTANCE OF TIMING
A common combined anesthetic induction technique includes fentanyl, propofol, and either succinylcholine or a nondepolarizing neuromuscular blocker such as rocuronium. Given that laryngoscopy and tracheal intubation can be one of the most stimulating events during a surgical procedure, it is useful to maximize the combined analgesic effect of drugs used for induction. A basic understanding of induction drug kinetics can guide the timing of drug administration (Table 28–1). Fentanyl has a different kinetic profile from propofol and succinylcholine. In order for each induction drug to reach maximal effect at nearly the same time, fentanyl 2 to 3 mcg/kg is administered 3 to 4 minutes before propofol.
|Fentanyl 2 mcg/kg bolus|
|Time to peak effect-site concentration||3.5|
|Time to probability of:|
|No response to laryngoscopy > 95%||Never|
|Loss of responsiveness > 95%||Never|
|Propofol 2 mg/kg bolus|
|Time to peak effect-site concentration||1.5|
|Time to probability of loss of responsiveness > 95%||0.5|
|Duration of probability of loss of responsiveness > 95%||4.5|
|Time to probability of no response to laryngoscopy > 95%||1|
|Duration of probability of no response to laryngoscopy > 95%||1.8|
|Time to probability of loss of responsiveness > 95%b||0.5|
|Duration of probability of loss of responsiveness > 95%||5|
|Time to probability of no response to laryngoscopy > 95%b||0.5|
|Duration of probability of no response to laryngoscopy > 95%||3.5|
A potentially attractive alternative to fentanyl during induction is remifentanil.1,2 Authors have suggested that remifentanil not only can be used as an analgesic for induction but also that this analgesia can be so profound that no neuromuscular blocking agent is required.2,3 A set of simulations comparing an induction sequence with propofol and remifentanil or fentanyl is presented in Figure 28–1.
The importance of timing. Simulation of induction techniques using propofol in combination with either remifentanil (top plots) or fentanyl (bottom plots). Simulations include the predicted effect-site concentrations (Ce levels) and the probability of loss of response to laryngoscopy for the bolus doses presented in the graphs. The fentanyl was administered 4 minutes before the propofol, so that both agents would reach near-peak concentrations at the same time. With the addition of an opioid, the duration of effect for loss of response to laryngoscopy is prolonged (see Figure 28–2). This set of simulations assumes a 30-year-old, 100-kg, 183-cm male. Simulations were based on published pharmacokinetic and pharmacodynamic models.4,5,6,7,8, and 9
In this simulation, fentanyl is administered 4 minutes before the propofol, such that both agents reach their peak concentrations at nearly the same time (third plot from the top). Similarly, remifentanil is administered with the propofol. Propofol and remifentanil have a very similar kinetic profile when administered as a bolus, such that they reach their respective peak concentrations at nearly the same time (top plot). The simulations also present the predicted time course of no response to laryngoscopy. Of note, both opioids prolong the duration of this effect in a dose-dependent fashion. As dosed, they prolong the effect by 1 to 2 minutes. Although remifentanil has a rapid onset and offset, as dosed in these simulations, it does not appear to be any different from fentanyl in the duration of effect.
Remifentanil may lead to pronounced respiratory depression. In comparison to fentanyl, remifentanil’s rapid onset does not allow for an accumulation of carbon dioxide as occurs with fentanyl. Elevated carbon dioxide levels can offset the respiratory depressant effects of opioids to some degree. Patients may not spontaneously breathe during the early phases of induction as they would with fentanyl. Another consideration with remifentanil is that when administered as a bolus, it can have a potent vagal effect, causing bradycardia. Caution should be used when administering large boluses. It may be prudent to administer boluses slowly in patients with known or suspected arrhythmias.
An exploration of the duration of no response to laryngoscopy for a range of propofol and opioid combinations is presented in Figure 28–2. This figure presents a remifentanil-propofol pharmacodynamic interaction model for loss or response to laryngoscopy and tracheal intubation. For a range of propofol (0–2 mg/kg), fentanyl (0–2 mcg/kg), and remifentanil (0–1 mcg/kg) combinations, predictions of the duration of effect are made. Of interest, at higher opioid concentrations, much less propofol is required to achieve an equivalent effect. Note that 1 mg/kg of propofol combined with remifentanil 1 mcg/kg provides a similar duration of effect to 2 mg/kg of propofol in the absence of any opioid. This is an example of the isoeffect line (black line in the figure), where any combination of sedative and opioid effect-site concentrations yields a similar effect.
Propofol–opioid combinations for induction. Topographic representation of the propofol–remifentanil pharmacodynamic interaction model for loss of response to laryngoscopy. The gray shaded areas represent portions of the response surface associated with a 5% to 50% (light gray), 50% to 95% (gray), and greater than 95% (dark gray) probability of effect. Superimposed over the interaction model surface are the approximate maximal concentration pairs (large circles) for each of the dosing regimens presented in Figure 28–1. The time each concentration pair is above a 95% probability of no response to laryngoscopy is presented within each circle in minutes. Fentanyl concentrations are presented as remifentanil equivalents.10 This set of simulations assumes a 30-year-old, 100-kg, 183-cm male. Simulations were based on published pharmacokinetic and pharmacodynamic models.4, 5, 6, 7, 8, and 9 Ce, effect-site concentration.
Two clinical implications of this set of simulations include:
For patients with a known or suspected condition that will lead to a rapid oxygen desaturation following apnea during induction, it may be prudent to select an opioid-propofol combination that quickly dissipates.
In patients where it is desirable to minimize the hemodynamic response to laryngoscopy, it may be useful to select a combination that best matches the duration of effect of the neuromuscular blocker.
When considering the clinical implications of an induction technique, it is useful to compare the duration of other effects such as loss of responsiveness and ventilatory depression. Figure 28–3 presents the time course of these effects for a conventional induction with fentanyl and propofol. These simulations illustrate the synergistic interaction between these 2 drugs. Propofol profoundly enhances and prolongs the analgesic effects of fentanyl, and fentanyl somewhat prolongs the sedative effects of propofol.
Predicted effects following induction with propofol 2 mg/kg and fentanyl 2 mcg/kg. The plot in A presents the time course of the effect-site concentrations (Ce levels). Fentanyl was administered 4 minutes before the propofol so that they would reach peak Ce levels at nearly the same time. The plots in B and C present the probability of unresponsiveness and intolerable ventilatory depression. For comparison, the plot in D presents the probability of loss of response to laryngoscopy from Figure 28-1. Unresponsiveness was defined as an observer’s assessment of alertness and sedation less than 2.11 Intolerable ventilatory depression was defined as respiratory rate less than 4 breaths/min.12,13 Plots B, C, and D present the predicted effects resulting from the fentanyl and propofol in combination and the effects from just propofol or fentanyl by themselves. This set of simulations assumes a 30-year-old, 100-kg, 183-cm male. Simulations were based on published pharmacokinetic and pharmacodynamic models.4,5,6,9,12,13,14 and 15