Anesthesiologists recognize the expanding role of premedication in optimizing patient’s condition prior to surgery. Important goals of premedication include reducing patient anxiety, providing analgesia as needed, facilitating induction of anesthesia, and optimizing patient comorbidities. This chapter will provide a brief overview of well-known premedication drugs, such as intravenous opioids and benzodiazepines, and explore how they interact with one another and how they may influence induction of anesthesia. This chapter will also review indications, controversies, and potential drawbacks of selected premedications used to manage common patient comorbidities.

Midazolam enjoys wide spread popularity among anesthesiologists because it has a rapid onset of anxiolysis with minimal side effects and provides anterograde amnesia. Midazolam is water-soluble, and unlike diazepam, does not cause irritation on injection. At relatively low doses (0.02 mg/kg), midazolam is an effective anxiolytic over a large age range (20–80 years), with minimal respiratory depression in healthy individuals of either gender.¹ Larger doses (0.05 mg/kg) increase the likelihood of sedation but are not more effective at reducing anxiety.¹ Elderly debilitated patients require up to 20% less midazolam (0.016 mg/kg) to achieve an equivalent anxiolytic effect.² For example, patients who have an American Society of Anesthesiologists (ASA) physical classification of 3 or greater and who are of age 55 or older should be dosed with caution.

An advantage of benzodiazepines is they attenuate catecholamine-induced stress response. For example, at doses of 0.025 mg/kg, midazolam attenuates stress responses; at 0.05 mg/kg it abolishes stress responses.³ This may be especially useful in patients with severe coronary artery or cerebral vascular disease who are at significant risk for catecholamine-induced ischemia.

Midazolam has an interesting kinetic profile (Figure 26–1). It has a rapid rise in effect-site concentration with intravenous administration in comparison to other benzodiazepines. However, it requires a relatively long time to reach peak concentrations (6–9 minutes), and plasma concentrations dissipate more slowly in comparison to other intravenous sedatives (eg, propofol). An anxiolytic effect is typically observed within minutes; clinicians may be tempted to administer additional midazolam if an effect is not observed within 2 minutes. Given that peak concentrations are not achieved for up to 6 minutes, additional doses may lead to more pronounced effect. For example, Figure 26–1 presents the anticipated effects from 2 doses of midazolam (0.025 mg/kg or 2 mg to an 80-kg individual) separated by 2 minutes using the Ramsay Sedation Scale (RSS).⁴ The RSS (range, 0–6) quantifies the effects of midazolam from anxiolysis (RSS = 2) to sedation (RSS = 3) to loss of responsiveness (RSS = 6). The additional midazolam dose prolongs reaching peak to 8 minutes and doubles the effect-site concentration, leading to an increased probability of sedation beyond just anxiolysis.

Opioids can decrease anxiety by ameliorating pain, a common preoperative issue. Opioids are often given in combination with midazolam. Fentanyl is frequently used because it is has a fast onset (peak effect within 5 minutes), short duration of action, and produces intense analgesia.

Midazolam interacts synergistically with fentanyl and other opioids. The analgesic and respiratory effects of fentanyl are pronounced in the presence of midazolam, and the anxiolytic and sedative effects of midazolam are pronounced in the presence of fentanyl.⁵ For example, in a study exploring the interaction between fentanyl and midazolam, fentanyl 2 mcg/kg by itself led to hypoxemia (SpO₂ < 90%) in half of recipients and midazolam 0.05 mg/kg caused no hypoxemia. When combined, however, essentially all study participants developed hypoxemia and half developed apnea.⁶ Other researchers confirmed this finding⁷ using similar dosing regimens for fentanyl (1.25 mcg/kg) combined with midazolam (0.05 mg/kg), emphasizing the importance of continuously monitoring patients when administering these drugs together.

Simulations of these dosing regimens visually illustrate the time course of effects presented in these reports (Figure 26–2) for a healthy male who stands 6 feet (183 cm)and weighs 176 pounds (80 kg). High-dose combinations (midazolam 0.05 mg/kg with fentanyl 2 mcg/kg) reach peak concentrations between 5 and 9 minutes. These doses in an 80-kg individual would be 4 mg of midazolam and 160 mcg of fentanyl and are perhaps higher than what anesthesiologists routinely administer. A high probability of analgesia is achieved within minutes and remains high for up to 1 hour. The probability of intolerable ventilatory depression (a respiratory rate less than 4 breaths/min) reaches a 40% probability within 5 minutes and then slowly diminishes over the next 30 minutes. As dosed, this combination of fentanyl and midazolam leads to a high probability of sedation for more than 40 minutes and a low probability of loss of responsiveness (< 20%) for 15 minutes. If using this dosing regimen for premedication, up to 30 minutes of continuous monitoring for apnea and hypoxemia would be prudent.

A more common dosing regimen is also presented in Figure 26–2. With midazolam 0.012 mg/kg and fentanyl 0.6 mcg/kg (approximately 1 mg of midazolam and 50 mcg of fentanyl in an 80-kg individual), the likelihood of analgesia is lower (25%–50%) for a much shorter period of time (< 15 minutes) compared to the high dose. The probability of intolerable ventilatory depression and loss of responsiveness is negligible. Some patients may develop sedation (15% probability) for 10 to 15 minutes.

If administered in temporal proximity to induction, premedicants may enhance induction drug effect. Both midazolam and fentanyl interact with propofol.⁵ One concern is that if during induction an unanticipated difficult airway is encountered, premedication may prolong emergence if it is necessary to wake up a patient rapidly.

To explore this concern, a simulation of premedication followed by induction of anesthesia 10 minutes later is presented in Figure 26–3. In this simulation, midazolam 0.025 mg/kg is administered 5 minutes prior to induction of anesthesia as a premedication. Five minutes later, induction of anesthesia begins with fentanyl 2 mcg/kg, followed 5 minutes later by propofol 2 mg/kg. Simulations present the time course of unresponsiveness and sedation with and without the midazolam and fentanyl.

As dosed, propofol renders 50% and 95% of patients unresponsive for 6 and 3 minutes, respectively. With the addition of midazolam and fentanyl, the duration of unresponsiveness for 50% and 95% of patients is extended to 9 and 5 minutes, respectively. Midazolam or fentanyl added to the propofol prolongs the duration by 1 minute compared to propofol alone. Waiting an additional 3 minutes for a patient to emerge from induction in an unanticipated difficult airway may be unacceptable in a setting of “can’t intubate and can’t ventilate.”

Midazolam and fentanyl substantially prolong sedation compared to propofol alone; their interaction is more pronounced than with loss of responsiveness. In these simulations, sedation is defined using the Observer’s Assessment of Alertness and Sedation Scale.⁸ Patients are considered sedated if they respond only after their name is called loudly or repeatedly. As dosed, propofol renders 50% and 95% of patients sedated for 7 and 4 minutes, respectively. With the addition of midazolam and fentanyl, the duration of sedation for 50% and 95% of patients is markedly extended to 44 and 24 minutes, respectively. Midazolam added to the propofol has minimal impact on the duration of sedation, but fentanyl added to the propofol prolongs the duration of sedation to 29 and 13 minutes for 50% and 95% of patients, respectively.

Another point of interest with premedicants is their impact on sedative–hypnotic dosing requirements for induction. Several researchers have explored how midazolam and/or fentanyl premedication, if administered near induction, decreases the amount of propofol needed to achieve loss of responsiveness.^{9, 10, 11, and 12}

How midazolam (0.025 mg/kg) as a premedicant and fentanyl (2 mcg/kg) as part of the induction influences the propofol dose is illustrated in Figure 26–4. In the presence of midazolam and fentanyl, the time course of unresponsiveness from propofol 0.5, 1, 1.5, and 2 mg/kg is compared to propofol 2 mg/kg alone. With both midazolam and fentanyl, the amount of propofol required to achieve a near-equipotent effect to propofol 2 mg/kg in terms of unresponsiveness is 1 mg/kg (Table 26–1). With either midazolam or fentanyl, as dosed, the amount of propofol required to achieve a near-equipotent effect is 1.5 mg/kg.