The ability to predict the effects of the drugs in our armamentarium demands an understanding of their pharmacokinetic and pharmacodynamic properties. This understanding is a fundamental prerequisite for the design of an effective sedation regimen and greatly increases the probability of producing the desired therapeutic effect. Context-sensitive half-time, effect–site equilibration time, and anesthetic/sedative drug interactions are fundamental concepts that are particularly useful in the context of monitored anesthesia care and will be discussed in some detail.

The ultimate objective of any dosing regimen is to deliver a therapeutic concentration of drug to its site of action, which is determined by the unique pharmacokinetic properties of that drug in that particular patient. The therapeutic response to a particular drug concentration is described by the pharmacodynamics of that particular patient–drug combination. There is a large degree of pharmacokinetic and pharmacodynamic variability, producing a significant variability in the dose-response relationship in clinical practice. Excessive sedation may result in cardiac or respiratory depression. Inadequate sedation may result in patient discomfort and potential morbidity from lack of cooperation. As a general principle, to avoid excessive levels of sedation, drugs should be titrated in small increments or by adjustable infusions rather than administered in larger doses according to predetermined notions of efficacy.⁴ In an ideal dosing regimen, an effective concentration of drug is achieved and then adjusted according to the magnitude of the noxious stimulus. If the noxious stimulus is increased or decreased, the concentration is increased or decreased accordingly. By the end of the procedure, the drug concentration should have decreased to a level compatible with rapid recovery. This approach requires the easily titratable drugs such as propofol. When using drugs such as propofol, adjustable-rate continuous infusions are the most logical method of maintaining a desired therapeutic concentration. When the traditional method of intermittent bolus administration is used, significant fluctuations in drug concentration occur. Under these circumstances, the plasma concentrations are either above or below the desired therapeutic range for a significant proportion of the procedure (Fig. 29-1). Continuous infusions are superior to intermittent bolus dosing because they produce less fluctuation in drug concentration, thus reducing the number of episodes of inadequate or excessive sedation. Administration of drugs by continuous infusion rather than by intermittent dosing also reduces the total amount of drug administered and facilitates a more prompt recovery.⁵

Following the administration of IV anesthetic drugs, the immediate distribution phase causes a brisk decrease in plasma levels as the drug is transported to the rapidly equilibrating vessel-rich group of tissues. There is a simultaneously occurring distribution of drug to the less well-perfused tissues such as muscle and skin. Over time, the drug is also distributed to the poorly perfused tissues such as bone and fat. Although the latter compartments are poorly perfused, they may accumulate significant amounts of lipophilic drugs during prolonged administration. This peripheral depot may contribute to a delayed recovery when the drug is eventually released back into the central compartment after its
administration is discontinued. Redistributive factors are important determinants of drug effect and influence the plasma concentration of a drug in a time-dependent fashion.

Until recently, the elimination half-time was the predominant pharmacokinetic parameter used as the predictor of an anesthetic drug’s duration of action. In everyday clinical practice, however, this parameter has not greatly enhanced our ability to predict anesthetic drug disposition. Only in single-compartment models does the elimination half-time actually represent the time required for a drug to reach half of its initial concentration after administration. In a single-compartment model, elimination is the only process that can alter drug concentration. Intercompartmental distribution cannot occur because there are no other compartments for the drug to be distributed to and fro. Most drugs in the anesthesiologist’s armamentarium are lipophilic and are, therefore, more suited to multicompartmental modeling than single-compartment modeling. Similarly, other pharmacokinetic parameters, such as distribution half-time, distribution volume, intercompartmental rate constants, and so forth, do not provide us with a practical means of predicting drug disposition. In multicompartmental models, the metabolism and excretion of some IV anesthetic drugs may have only a minor contribution to the changes in plasma concentration when compared with the effects of intercompartmental distribution.

The concept of context-sensitive half-time was developed to improve the description and understanding of anesthetic drug disposition.⁶ This concept has greatly improved our understanding of anesthetic drug disposition and is clinically applicable. The effect of distribution on plasma drug concentration varies in magnitude and direction over time and depends on the drug concentration gradients that exist between the various compartments. For example, during the early part of an infusion of a lipophilic drug, distributive factors will tend to decrease plasma concentrations as the drug is transported to the unsaturated peripheral tissues. Later, after the infusion is discontinued, drug will return from the peripheral tissues and re-enter the central circulation. The relative effect on plasma concentrations of distributive processes versus elimination varies over time and from drug to drug. The context-sensitive half-time describes the time required for the plasma drug concentration to decline by 50% after terminating an infusion of a particular duration.⁷ This parameter is calculated by using computer simulation of multicompartmental models of drug disposition (Fig. 29-2). The context-sensitive half-time reflects the combined effects of distribution and metabolism on drug disposition. There are several interesting aspects of these data. First, the data confirm the clinical impression that as the infusion duration increases, the context-sensitive half-time of all the drugs increases; this phenomenon is not described in any way by the elimination half-life. The increase in context-sensitive half-time is particularly marked with fentanyl and thiopental. In the case of fentanyl, drug that is irreversibly eliminated from the plasma by hepatic clearance is immediately replaced by drug returning from the peripheral compartments. Thus, although fentanyl has a shorter elimination half-life than that of sufentanil (462 vs. 577 minutes), its context-sensitive half-time is much greater than that of sufentanil after an infusion of longer than 2 hours. The storage and later release of fentanyl from peripheral binding sites delay the decline in plasma concentration that would otherwise occur. The context-sensitive half-times of all the drugs bear no constant relationship to their elimination half-times. Compare also the context-sensitive half-times of propofol and thiopental (Fig. 29-2). Although the context-sensitive half-times of propofol and thiopental are comparable following a brief infusion, the context-sensitive half-time of thiopental increases rapidly following all but the shortest infusions. This finding confirms the clinical impression that thiopental is not an ideal drug for continuous infusion during ambulatory procedures. The context-sensitive half-time of propofol is prolonged to a minimal extent as the infusion duration increases. After an infusion of propofol, the drug that returns to the plasma from the peripheral compartments is rapidly cleared by metabolic processes and is, therefore, not available to retard the decay in plasma levels. This difference between thiopental and propofol is attributable to (1) the high metabolic clearance of propofol compared with thiopental, and (2) the relatively slow rate at which propofol returns to the plasma from peripheral compartments.

Alfentanil is the opioid that has, until recently, been most frequently studied, described, and promoted in the context of ambulatory techniques. Alfentanil has a very short elimination half-time, one-fifth that of sufentanil (111 vs. 577 minutes). However, despite the longer elimination half-time of sufentanil, its context-sensitive half-time is actually less than that of alfentanil for infusions up to 8 hours in duration. This phenomenon is explained in part by the huge distribution volume of sufentanil. After termination of a sufentanil infusion, the decay in plasma drug concentrations is accelerated not only by elimination but also by the continued redistribution of sufentanil into peripheral compartments. On the other hand, the small distribution volume of alfentanil equilibrates rapidly; therefore, peripheral distribution of drug away from the plasma is not a significant contributor to the decay in plasma concentration after an infusion. The data derived from computer simulation by Hughes et al.⁵ show that the plasma decay of alfentanil is slower than that of sufentanil following infusions of similar duration to those used during
conscious sedation. Thus, despite its short elimination half-time, alfentanil may not necessarily be superior to sufentanil.⁸

Over the past 30 years, propofol has become a popular choice for monitored anesthetic care due to its side effect profile and ease of titratability. Propofol has many of the ideal properties of a sedative–hypnotic for use in monitored anesthesia care. Its pharmacokinetic profile, that is, a context-sensitive half-time that remains short even after infusions of prolonged duration and a short effect–site equilibration time makes it an easily titratable drug with an excellent recovery profile. The quality of recovery and the low incidence of nausea and vomiting make propofol particularly well suited to ambulatory monitored anesthesia care procedures. A significant body of experience with the use of propofol for monitored anesthesia care has emerged. Propofol has significant advantages compared with benzodiazepines when used as the hypnotic component of a monitored anesthesia care technique. Although midazolam has a relatively short elimination half-time, its context-sensitive half-time is approximately twice that of propofol. Whereas propofol is noted for the rapid return to clear-headedness midazolam is often associated with prolonged postoperative sedation and psychomotor impairment, particularly in the elderly. Propofol in typical monitored anesthesia care doses (25 to 75 μg/kg/min) has minimal analgesic properties although propofol use during anesthesia has been associated with less postoperative pain and narcotic use when compared to isoflurane.³⁰ However, the unique advantages of propofol can be exploited to the maximum when propofol is used to provide sedation when the analgesic component is provided by a local or regional analgesic technique. The use of propofol (50 to 70 μg/kg/min) to provide sedation (defined as sleep with preservation of the eyelash reflex and purposeful reaction to verbal or mild physical stimulation) as an adjunct to spinal anesthesia for lower limb surgery has been examined.³¹,³²,³³ After termination of infusions of approximately 100 minutes, patients regained consciousness in approximately 4 minutes. The authors also noted the ease with which general anesthesia could be induced if necessary by increasing the propofol infusion. The same group also compared propofol (60.5 μg/kg/min) with midazolam (4.3 μg/kg/min) as an adjunct to spinal anesthesia. The propofol group had faster immediate recovery than the midazolam group (2.3 vs. 9.2 minutes to spontaneous eye opening). Furthermore, psychomotor function was comparable with baseline values following propofol
sedation but did not return to baseline until 2 hours after midazolam administration. Several studies comparing propofol and midazolam sedation for local and regional anesthesia demonstrated that propofol produced less postoperative sedation, drowsiness, confusion, and clumsiness than midazolam but that discharge times varied.³⁴,³⁵

General anesthesia with propofol is generally associated with less nausea and vomiting than most other anesthetic techniques.³⁶,³⁷,³⁸,³⁹,⁴⁰,⁴¹ There is growing evidence that even subhypnotic doses of propofol also possess direct antiemetic properties particularly when combined with an antiemetic in patients at risk for nausea and vomiting.⁴²,⁴³,⁴⁴,⁴⁵ Thus, it is likely that the beneficial effects of propofol upon nausea and vomiting will be a feature of monitored anesthesia care techniques using this drug. On the other hand, even during low-dose infusions used for sedation, pain during injection of propofol may be troublesome in 33% to 50% of patients.³⁵,⁴⁶ Several strategies for reducing the pain of propofol administration are described in Table 29-1.⁴⁷

In December 2008, fospropofol, a prodrug of propofol, was approved by the FDA for use during monitored anesthetic care, but at this time, it has not been extensively studied. This phosphate ester prodrug is metabolized by endothelial cell alkaline phosphatases to intermediate metabolites of propofol, formaldehyde, and phosphate.⁴⁸,⁴⁹,⁵⁰ Recent publications on the pharmacodynamics and pharmacokinetics of fospropofol were retracted due to an error discovered in the analytical propofol assay.⁵¹,⁵²,⁵³ It is known that the active metabolite of propofol has a Cmax value of 4 minutes which is longer than the lipid-based fospropofol formulation. Information obtained from the manufacturer’s website listed the terminal phase elimination half-life (t_1/2) of fospropofol as 0.81 ± 0.08 and 0.88 ± 0.08 hours in healthy subjects and patients, respectively. In healthy subjects, the apparent total body clearance of liberated propofol was 1.95 ± 0.345 L/hr/kg and t_1/2 was 2.06 ± 0.77 hours. In patients, clearance of fospropofol was 0.31 ± 0.14 L/hr/kg, and clearance for propofol was 2.74 ± 0.80 L/hr/kg and is similar to that observed in healthy subjects. Pharmacokinetics of fospropofol does not appear to be affected by patients with mild to moderate renal insufficiency. At this time, it has not been studied in patients with hepatic impairment.

The standard dosing regimen recommended by the manufacturer Eisai is an initial IV bolus dose of 6.5 mg/kg followed by supplemental doses of 1.6 mg/kg as needed. No initial dose should exceed 16.5 mL; no supplemental bolus should exceed 4 mL. If patients are greater than 65 years of age or classified as ASA physical status 3 or 4, a modified dosing regimen (a 25% reduction of the standard dose), should be administered. Supplemental doses should only be administered after patients can demonstrate movement upon command (verbal or tactile stimulation) and not more frequently than every 4 minutes (accessed from Eisai website January 2012 URL http://us.eisai.com/product.asp?ID=274).

At the time of this writing, there are limited numbers of clinical control trials to evaluate the safety and efficacy of fospropofol for short procedures requiring monitored anesthesia care. Cohen et al.⁵⁴ conducted a randomized controlled multicenter trial of 127 ASA PS range from 1 to 4 undergoing colonoscopy. The investigators randomized patients into two main treatment arms (fospropofol vs. midazolam). The fospropofol group was further randomized into one of four treatment arms of increasing doses of fospropofol (2 mg/kg, 5 mg/kg, 6.5 mg/kg, or 8 mg/kg). All patients were pretreated with 50 μg of fentanyl. They concluded that the optimal dose to provide moderate sedation was 6.5 mg/kg. The higher dose of 8 mg/kg met the criteria for deep sedation and was not necessary in order to complete the procedure. The most common adverse effects reported included paresthesias described as a burning sensation in the perineal and perianal area, pruritus, hypoxemia, hypotension, and abdominal pain. An additional follow-up publication by the same investigators analyzed 314 patients and concluded that the appropriate dose for moderate sedation was 6.5 mg/kg. At this dosage, they reported a 4% incidence of deep sedation.⁵⁵

Fospropofol was also studied as the sedative agent for patients undergoing bronchoscopy. This study is a multicentered double blinded randomized controlled study of 252 patients classified as ASA P1 to P4 undergoing flexible bronchoscopy. All patients received 50 μg of fentanyl prior to the administration of either 2 mg/kg or 6.5 mg/kg fospropofol. The investigators reported a higher success rate with the higher dose of 6.5 mg/kg compared to 2 mg/kg (88.7 vs. 27.5% respectively; p < 0.001). The most common adverse events reported included paresthesias (47.6%), pruritus (14.7%), hypoxemia (14.3%), and hypotension (3.2%). Approximately one-third of patients who received the 6.5 mg/kg dose required some form of airway support. There was a higher satisfaction rate of both physician and patient when the 6.5 mg/kg dose was administered.

It should be noted that these studies were fully sponsored by the manufacturer and conducted by nonanesthesiologists. One of the investigators is a consultant for the manufacturer MGI/Eisai corporation. The manufacturer attempted to obtain FDA approval for nonanesthesiologists to provide fospropofol for monitored anesthesia care; however, this request was later denied. The Drug Enforcement Administration listed fospropofol as a class IV controlled substance.

Benzodiazepines are commonly used during monitored anesthesia care for their anxiolytic, amnestic, and hypnotic properties. Patients presenting for diagnostic and surgical procedures frequently request some form of anxiolytic. Midazolam is usually administered prior to the start of the surgical or diagnostic procedures to facilitate amnesia and reduce the patient’s level of anxiety. Compared to other benzodiazepines, midazolam’s relatively
short elimination half-life and decreased likelihood of concomitant drug interactions makes this a superior choice to other benzodiazepines. The important differences between midazolam and diazepam are listed in Table 29-2.⁵⁶ Although midazolam has a short elimination half-time, there is often significant and prolonged psychomotor impairment following sedation techniques using midazolam as a significant component. With the recent availability of propofol, midazolam may be better used in a modified role by using lower doses prior to the start of a propofol infusion to provide the specific amnestic and perhaps anxiolytic component of a “balanced” sedation technique rather than as the major hypnotic component.⁵⁷ A study in healthy volunteers demonstrated that propofol reduced the distribution and clearance of midazolam in a concentration-dependent manner. The group reported increased plasma levels of midazolam ranging from 5% (±14.7%) to 26% (±9.4%) during increasing doses of propofol for monitored anesthesia care. This strategy allows the more evanescent and titratable propofol to provide the desired level of deep sedation in an adjustable manner according to the specific stimulus. The analgesic component, if required, of a balanced monitored anesthesia care technique may be provided by regional/local techniques or opioids. Again, when using opioids with benzodiazepines, the potential for significant respiratory impairment should be considered.

Age of the patient should be taken into consideration when administering benzodiazepines. The dose of a particular benzodiazepine required to reach a desired clinical end point is reduced in elderly compared with younger patients.⁵⁸ This difference in dosing requirements in elderly patients is mainly related to pharmacodynamic factors. As demonstrated by the threefold decrease in plasma concentration of midazolam, 50% of patients would be expected not to respond to verbal command (Cp50) in an 80-year-old patient compared with a 40-year-old patient (Fig. 29-4).⁵⁹

Benzodiazepines are valuable components of monitored anesthesia care techniques because they enhance patient comfort, improve operating conditions, and provide amnesia. However, recovery of psychomotor and cognitive function may be significantly prolonged following benzodiazepine sedation, especially when compared with sedative–hypnotic techniques using propofol as the major component.⁶⁰ The specific benzodiazepine antagonist flumazenil provides the potential to improve the recovery profile of benzodiazepines by permitting the active termination of their sedative and amnestic effects without invoking adverse side effects. However, the potential for resedation remains an obstacle to the routine use of benzodiazepine reversal, particularly in patients undergoing ambulatory procedures. The effects of midazolam may recur up to 90 minutes following the administration of flumazenil.⁴⁶ Thus it is possible that patients could be discharged prematurely to a less well-monitored area, or even out of the hospital in the case of ambulatory surgery, and later experience recurrence of benzodiazepine effects. An important additional issue is that of cost. The routine use of flumazenil-antagonized benzodiazepine sedation has a significant cost disadvantage. Ghouri et al.⁴⁶ demonstrated that flumazenil-antagonized midazolam sedation was more expensive than propofol sedation ($68.67 vs. $27.80). Typical dose requirements for use of flumazenil are listed in Table 29-3.

Opioids are administered in the context of monitored anesthesia care to provide the specific analgesic component of a “balanced” technique. Opioids are indicated when regional or local anesthetic techniques are inappropriate or ineffective and are typically administered immediately prior to the painful or invasive
portion of the procedure. In addition, opioids may be indicated to blunt untoward hemodynamic and physiologic responses, a desirable effect in patients with significant cardiac disease. Pain relief may be required for factors other than the procedure itself, such as uncomfortable positioning, propofol injection, pneumatic tourniquet pain, or other pain not relieved by the local anesthetic technique. The choice of a particular opioid depends on several factors including cost, availability, time of onset, duration, and potential side effects. Opioids frequently administered during monitored anesthesia care include alfentanil, fentanyl, and remifentanil. Their adverse effects include respiratory depression, muscle rigidity, and nausea and vomiting, all of which are undesirable in the spontaneously breathing patient with an unprotected airway. A complicating issue is that the ability to predict the effect of a given dose of opioid in a particular patient is limited by significant interpatient pharmacokinetic and pharmacodynamic variability. Furthermore, the coadministration of sedative agents increases the risk of serious adverse events, particularly respiratory arrest. This problem is usually overcome in practice by the cautious incremental administration of small, carefully titrated boluses or by titrating infusions to the desired effect.