Opioid receptors
Receptor
Site of analgesic action
Action
Mu1
Supraspinal
Analgesia, euphoria, confusion, and nausea
Mu2
Spinal analgesia and supraspinal (brain stem) actions
Respiratory depression, cardiovascular (bradycardia) and gastrointestinal effects (slow motility), miosis, and urinary retention
Delta
Supraspinal and spinal
Analgesia, cardiovascular depression, decreased brain and myocardial oxygen demand
Kappa
Supraspinal and spinal
Analgesia, dysphoria, psychomimetic effects
Respiratory depression, nausea, vomiting, pruritis, as well as chest rigidity are among the reported complications of opioid use even in a non-dose related fashion.
Several opioid analgesics are frequently used in MAC sedation cases, including morphine, fentanyl, meperidine, and hydromorphone, as well as the newer rapid onset opioids such as remifentanil, alfentanil, and sufentanil.
The onset as well as the duration of action are among the important factors that dictate which opioid to use in MAC sedation cases. Morphine has a slow onset and prolonged effect making it a poor choice for a MAC sedation case due to the difficulty in titration of its dose to the desired effect. Its long duration of action might make morphine a reasonable choice when significant pain is expected postoperatively.
Fentanyl has a relatively rapid onset and short duration of action, making it a good choice for analgesia in MAC sedation cases. It is commonly used in repeated intravenous boluses or as a continuous IV infusion. The bolus doses are usually 0.5–1 mcg/kg and the intravenous infusion is usually 0.01–0.05 mcg/kg/h. Fentanyl is potent and has a relatively predictable effect, making it a drug of choice in procedural sedation by endoscopists, radiologists, and also by anesthesiologists.
Hydromorphone can be used as an IV bolus in increments of 0.2–0.4 mg combined with other sedatives. It is also reported to be used for mechanically ventilated pediatric patients for ICU sedation and pain control as a continuous IV infusion. The usual starting dose for IV infusion is 1 mcg/kg/h and can be titrated up to a maximum dose of 8 mcg/kg/h.
Meperidine used to be one of the most widely used analgesics in moderate procedural sedation for endoscopy—commonly used as an IV bolus of 25–100 mg. Meperidine causes tachycardia due to its atropine-like action that can confuse the picture of inadequate sedation and/or analgesia. In small doses, meperidine has a desirable anti-shivering action. Gastroenterologists were familiar with the use of meperidine but with the current practice, where more anesthesiologists are involved in the sedation of this patient population, the older medications with the slow onset characteristics are becoming rarely used in MAC sedation cases, as they are being replaced by more potent analgesics with a rapid onset and short duration of action. Relatively newer opioids such as remifentanil, alfentanil, and sufentanil are gaining more popularity in MAC sedation cases, as they all share in common a rapid onset and short duration of action, making them suitable for different procedures—especially those with an unpredictable duration—as these medications are used as continuous IV infusion. Remifentanil has been used frequently as a sole sedative as well as in combination with other short-acting sedatives such as propofol. Remifentanil has a unique property among other opioids, which is its metabolism by nonspecific esterases causing a rapid and uniform clearance even with a prolonged administration, especially in the sedation of ICU patients. Remifentanil is commonly used as a continuous infusion in a dose 0.05–0.1 mcg/kg/h with or without an initial bolus of 0.5–1 mcg/kg.
Alfentanil is another synthetic opioid analgesic with a rapid onset and short duration of action. It also can be used as IV boluses of 5–10 mcg/kg or as a continuous infusion of 0.25–1 mcg/kg/min. Alfentanil is usually combined with propofol in MAC sedation cases to provide successful sedation and adequate analgesia.
Both alfentanil and remifentanil have the disadvantage of the rapid offset of analgesic effect. So although they provide fast, potent, and reliable analgesia in painful procedures, their analgesic effects do not last for a long time after the termination of the infusion at the end of the procedure, leaving the patient in significant pain. Thus it is recommended to give a longer acting analgesic during the procedure in addition to these opioids to ensure the patient’s comfort in the post-procedure period.
Sufentanil is the most potent synthetic opioid, with an estimated potency of 5–15 times more than fentanyl. It can be used as IV boluses of 0.1–0.5 mcg/kg and a continuous infusion of 0.005–0.01 mcg/kg/h. Sufentanil has the advantage of longer lasting postprocedure analgesic effect that lasts longer that fentanyl with less respiratory depression effects. Sufentanil causes non-dose-dependent bradycardia and hypotension due to its cardiovascular depressive action.
All opioids (especially rapid onset synthetic ones) suppress the gag reflex, which is beneficial in upper endoscopic procedures.
26.2.5 Ketamine
Ketamine is an IV anesthetic with significant analgesic, amnestic, and sedative effects. Ketamine exerts its action by blocking the membrane effects of the excitatory neurotransmitter glutamic acid at the N-methyl-D-aspartate (NMDA) receptor subtype, causing a dissociative anesthesia. It has the advantage of the preservation of spontaneous breathing and airway reflexes, but hypoventilation as well as a short period of apnea has been reported with larger doses. Its onset of action after a single IV bolus is 30–60 s, and its peak effects is in 1 min and duration is 15 min. Ketamine causes emergence phenomenon in 10–20% of cases where postoperative disorientation, sensory and perceptual illusions, and vivid dreams happen. Emergence phenomenon can be attenuated by the co-administration of other sedatives such as propofol, barbiturates, or benzodiazepines with ketamine during MAC sedation cases.
The IV general anesthesia induction dose of ketamine is 2 mg/kg, but sedation and analgesia can be provided by an IV dose of 0.2–0.8 mgs/kg. The analgesic effect of ketamine lasts in the postoperative period, decreasing the need for postoperative analgesics.
Ketamine increases myocardial oxygen consumption, increases intracranial and intraocular pressures, and increases salivation. All these effects together with the possibility of emergence phenomenon make the use of ketamine in the MAC sedation cases less favorable.
26.2.6 Dexmedetomidine
Dexmedetomidine is a relatively new sedative with some analgesic and amnestic properties that was first introduced in 1999. It works on the α(alpha)2 receptors as an agonist. Dexmedetomidine is used as a continuous infusion at a rate 0.2–1 mcg/kg/h with or without an initial loading dose of 0.5–1 mcg/kg over 10 min. After the initial bolus, its onset of action is 5–10 min, with peak effect in 15–30 min. Duration of action is dose dependent.
Dexmedetomidine has several advantages:
It has a moderate analgesic action, even when used in a small dose.
Patients sedated with dexmedetomidine, tend to be easily arousable and cooperative though still comfortable. This property is advantageous in cases where patients’ cooperation is helpful, such as during awake intubation using the fiberoptic scope [10].
It has a potent antisialagogue action making it desirable in cases of airway instrumentation.
It has limited amnestic properties.
It allows respiratory stability, even in deep levels of sedation, where patients usually maintain adequate ventilation.
The main disadvantages of dexmedetomidine are bradycardia and hypotension due to its α(alpha)2 agonist action. These cardiovascular effects are more pronounced in old age, especially when bolus doses are used and in cases of higher infusion doses. It also has slower onset and delayed recovery than other commonly used sedatives such as propofol.
26.2.7 Fospropofol Disodium
Fospropofol is a water-soluble prodrug of propofol that was recently introduced as a sedative. It interacts with the enzyme alkaline phosphatase to release propofol. Its delayed and non-acute peak effects add to its safety. Its recommended dose is 4.9–6.5 mgs/kg as a bolus dose followed by supplemental doses of one-fourth the initial doses no more frequent than every 4 min as needed. Patients are dosed according to their weight if their weight is 60–90 kg, and patients who weigh less than 60 kg are dosed as if they are 60 kg. The dose per kg caps at 90 kg and patients who weigh more than 90 kg are dosed as if they weigh 90 kg.
Initial trials of fospropofol use in sedation are promising [11], due to its relatively good safety margins, and less painful injections compared to propofol, as well as the absence of the propofol lipid load in cases of prolonged use.
Fospropofol causes high incidence of pruritus and paresthesia (mainly perineal or genital), and it can also cause hypotension, headache, and hypoxemia.
US Food and Drug Administration (FDA)-approved prescribing information for fospropofol (Lusedra®) states, “Lusedra should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the diagnostic or therapeutic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation.” [12].
26.3 Monitored Anesthesia Care Techniques
There are different techniques used to provide monitored anesthesia care to the patients. The choice of the appropriate technique is usually dependent on several factors:
The experience and preference of the anesthesia care provider
The age and physical status of the patient
The length and nature of the procedure and the expected pain associated with the procedure
The needed level of patients’ cooperation and level of sedation
Nature of the procedure room, setting, access to the patient, and its proximity to the recovery room
Special equipments availability, such as anesthesia machines and infusion pumps such as target-controlled infusion pumps (TCI).
26.3.1 Intermittent Intravenous Bolus Technique
This is one of the easiest, simplest, and most widely used MAC sedation techniques. The main advantage of this technique is its simplicity that makes it an attractive choice in minor, short procedures on young healthy patients who can tolerate the administration of intermittent IV boluses of relatively longer acting sedatives and analgesics (e.g., benzodiazepines, opioids, and fospropofol) to reach the desired level of sedation.
This technique might not be suitable for older, debilitated, or chronically ill patients where the safety margins with medications are narrow. Also, it is not a favorable technique in morbidly obese patients or patients with significant obstructive sleep apnea who can be oversensitive to the load of a bolus medication. In these patients slow IV infusions provides a better titration option.
Patient controlled sedation (PCS) is one of the intermittent bolus techniques tried for sedation with the suggested advantage of avoiding over- or under-sedation. In 2 trials comparing propofol PCS with anesthesiologist-controlled sedation, both methods provided comparable satisfaction levels. However, PCS was associated with lower mean calculated plasma concentrations of propofol in one report [13] and the second study reported significantly lower total propofol dose [14].
26.3.2 Continuous Infusion Technique
Providing IV sedatives, anesthetics, and/or analgesics in a continuous infusion pattern has several advantages:
Provides a more predictable plasma drug concentration
Provides more cardiopulmonary stability, especially for older or debilitated patients, thus reducing the need for vasoactive medications
Reduces the need for supplemental anesthetics
Lowers the total agent’s doses used, resulting in faster recovery times
This technique is mainly suitable for newer fast-onset and short-acting sedatives and analgesics, where these agents can also be used in combinations (propofol/remifentanil, propofol/alfentanil, or ketamine/propofol).
26.3.3 Target-Controlled Infusion Technique
The main concept of target-controlled infusion (TCI) is controlling a specific drug concentration in a specific compartment or end organ; this concentration is referred to as the target concentration. This target infusion rate needed to achieve a targeted concentration is determined using a complex computer system that uses the different pharmacokinetic models of the sedatives studied in volunteers or actual patients whose physical statuses are mostly ASA classes 1 and 2. These drugs’ information are stored in the software of the machine and using multi-compartment kinetic models, as well as the variances in age, weight, height, and sex of different patients, calculated doses are determined by the TCI pumps according to the selected target level. Using this technique allows the computer in the pump to automatically calculate and control the infusion pump medication delivery rate to reach and maintain the target plasma concentration selected. Target concentrations can be adjusted over time based on the clinical need and patient response.
The accuracy and success of a TCI system is dependant on the medication’s information data stored in the software. This information is derived from the medical literature and is, to a big extent, dependent on studies done on actual patients and volunteers who are usually healthy.
The TCI system can also incorporate a specific patient’s cardiac output and hepatic function into the dosing models, making it unique in adjusting the sedatives needed to the patient’s expected handling of these medications.
Due to the considerable inter-patient variability in both pharmacodynamics and pharmacokinetics, especially in older and chronically debilitated patients, the TCI systems are still dependant on data stored in the software that might not reflect the actual patient parameters.
Propofol is still the most used medication in this system.
26.3.4 Closed Loop Technique
The closed loop technique works by automatically administering sedatives guided by the Bispectral Index™ (BIS™) monitoring reading. It is still under investigation as a modification to the TCI system, which is considered an open loop system. The system adjusts the dose of sedative given and its target concentration according to the effect measured by the BIS number. The system is being evaluated both in the ICU as well as in the procedure room with promising results. The system aims at delivering minimum amounts of sedatives allowing for sedation, thus decreasing the side effects. Again, this technique is still under trial and not yet widely used in practice [15].
26.4 Perioperative Management
26.4.1 Fasting Time Guidelines
Sedation and general anesthesia is a continuum; so the same fasting duration required for general and regional anesthesia is also required for MAC sedation cases. The limited ability to predict different patients’ responses to sedatives and to surgical stimulation necessitate that the patients who are planned to have sedation and MAC follow the same fasting guidelines as general anesthesia cases. Special attention should be paid to the level of sedation planned for patients with a history suggestive of gastroesophageal reflux disease (GERD), delayed gastric emptying, and potentially full stomach to minimize the risk of pulmonary aspiration.
26.4.2 Preoperative Evaluation
A significant number of cases done outside of the main operating rooms suite are cared for under MAC sedation. This fact caused a major and a common misconception that these patients do not need a formal pre-anesthesia evaluation like general anesthesia cases.
Pre-anesthesia evaluation guidelines should always apply to MAC sedation cases. Moreover, the pre-procedure evaluation of the procedure room, location, equipment, and personnel, as well as the availability of recovery rooms and emergency equipment, should all be evaluated before starting patient care.
Pre-procedure patient evaluation should focus on medical conditions, medication allergies, NPO status, and previous anesthesia-related complications for the patient or his family. Airway, chest, and cardiac examination should also take place. Relevant investigations should be reviewed.
Planned level of sedation, and degree of anesthesia intervention should be discussed with the patient and the physician performing the planned procedure before starting the sedation and the procedure. Questions and concerns from the patient’s point of view should be addressed by the anesthesiologist at that time.
The anesthesiologist should also pay special attention to the candidacy of the patient for MAC sedation, as appropriate patient cooperation and motivation are of crucial importance to the success of the procedure and the patient’s satisfaction as well.
There are certain conditions that make MAC sedation challenging or inappropriate such as:
Impaired patient cooperation due to extremes of age, altered mental status, severe pain or discomfort, intoxication, or systemic or psychiatric diseases affecting the cognitive function of the patient.
Factors related to the patient’s positioning during procedure, such as inability to lie still or flat, or procedure requiring uncomfortable positioning for a prolonged period of time.
Nature of the procedure, like in procedures where minor movements will be detrimental to the patient’s safety, examination accuracy, or procedure success. Also procedure where expected blood loss or cardiopulmonary instability are highly expected.
Suspected or known difficult airway management, when more than minimal sedation is expected to be required for the procedure.
26.5 Intraoperative Management
In the effort to improve, guide, and standardize the anesthesia and patient care practices, the ASA came up with recommendations, statements, and guidelines. In 1986 the ASA approved the standards of basic anesthetic monitored, which was last amended in 2010 and affirmed on October 28, 2015 [16]. They identified 2 standards:
Standard 1 – It stressed the importance of continuous presence of a qualified anesthesia care provider throughout the conduct of all general anesthetics, regional anesthetics, and monitored anesthesia care.
Standard 2 – During all anesthetics (including MAC sedation) oxygenation, ventilation, and circulation should be continually evaluated for all patients. They also identified the recommendations for ideal ways of monitoring that might differ from one type of anesthetic to the other. For oxygenation, although the inspired oxygen concentration in the breathing circuit should be monitored for patients under GA, only a quantitative method of measuring tissue oxygenation by a pulse oximetry is feasible and suitable for MAC sedation cases. They stressed the importance of audible variable pitch pulse tones and adequate illumination to assess the patients’ color.
During moderate or deep sedation in MAC cases, the adequacy of ventilation should be evaluated by continual observation of qualitative clinical signs and monitoring for the presence of exhaled carbon dioxide, unless precluded or invalidated by the nature of the patient, procedure, or equipment.
Continuous assessment of circulation by means of heart rate and blood pressure monitoring at least every 5 min is mandated during all anesthetics.
Temperature monitoring is mandated in cases where significant body temperature changes are expected or intended.
26.5.1 Monitoring Depth of Sedation
Continuous monitoring of the depth of sedation is very important for ensuring the safety and effectiveness of sedation during MAC, both in the operating room as well as in procedure rooms. The most basic way of monitoring the depth of sedation is the continuous clinical assessment of the patient. Clinical assessment of a patient’s response to verbal and tactile stimulation is very important. Observing eyelash reflexes, papillary responses, tearing, and the pattern of respiration are all helpful in evaluating the level of sedation.
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