Clinical Pharmacology

Benzodiazepines are gamma aminobutyric acid (GABA) receptor agonists that increase the affinity of these receptors for the GABA ligand. This in turn results in an increase in the frequency with which the chloride channels open, allowing intracellular influx of chloride ions. The influx of chloride ions hyperpolarizes postsynaptic neurons, inhibiting their ability to produce an action potential. Similar to fentanyl, midazolam is metabolized by the CYP3A4 enzyme in the liver and intestines into water-soluble, glucuronidated end products and is excreted principally in urine.

Indications and Usage

Outside of the operating room, labeled indications include sedation, anxiolysis, and amnesia. Midazolam is indicated for the initiation of general anesthesia before the administration of any other medications, as well as maintenance of anesthesia as a component of a balanced anesthesia technique.

Dosage and Administration

When used in conjunction with other medications in a balanced anesthetic technique, midazolam is typically administered up to a 0.05 to 0.10 mg/kg dose, which is divided up into smaller boluses titrated to effect. Additional 0.5 mg to 1 mg boluses can be given intermittently to ensure adequate sedation for the duration of the procedure.

Contraindications

Fortunately, the contraindications for the use of midazolam are limited to patients with known hypersensitivities, acute narrow-angle glaucoma, hypotension, and shock. ^,

Warnings and Precautions

As other sedatives, midazolam, classified as a controlled substance IV, can cause central nervous system (CNS) depression, cardiovascular and respiratory depression, and obstructive and central apnea. Individualized anesthetic plans should be devised for each patient. Clinical vigilance is required along with the application of all indicated monitoring devices so that the patient can be monitored throughout the procedure and until full recovery. An oxygen source, resuscitative medications, appropriate bag-valve-mask, and advanced airway equipment should be easily accessible in case an airway or cardiovascular event occurs.

Adverse Reactions

The most common adverse reactions to midazolam include hiccups, coughing, nausea, vomiting, thrombophlebitis, thrombosis, disinhibition, respiratory depression, hypotension, tachycardia, and pain on injection.

Drug Interactions

Midazolam should be avoided or subject to dose modification for patients taking other CNS depressants. Midazolam is metabolized by CYP3A4 enzymes, so concurrent use of CYP3A4 inhibitors such as diltiazem, verapamil, erythromycin, and cimetidine can lead to prolonged sedation. Although these agents and others that have gained attention, such as grapefruit juice, may lead to increased blood levels of midazolam, the clinical significance is likely minimized when the drug is used intravenously with careful titration to the desired level of sedation.

Use in Specific Populations

Midazolam carries a Food and Drug Administration (FDA) risk factor “D” for pregnant patients. Chronic benzodiazepine use should be avoided in pregnant patients, as a correlation with increased incidence of cleft palate, CNS defects, and dysmorphism exists in the current literature. Although studies suggest that a single dose is unlikely to produce harm, benzodiazepine administration during the second and third trimesters has been shown to be associated with neonatal withdrawal syndrome and floppy infant syndrome.

Nursing mothers have historically been advised to stop breast feeding for 24 hours following administration of benzodiazepines. However, more recent data have shown that this is not necessary. ^, In 2019, the American Society of Anesthesiologist’s Committee on Obstetric Anesthesia published a recommendation for nursing patients to resume breastfeeding following administration of anesthesia, because the anesthetic agents used are excreted in breast milk at only very low levels.

As with other sedation medications, consideration for decreased dosing should be made for geriatric patients, as they tend to have higher peak plasma concentrations of benzodiazepines than nongeriatric patients.

Accumulation of midazolam and its active metabolites can occur in patients with renal and hepatic impairment, leading to excessive sedation and toxic accumulation. An assessment of kidney and liver function must be performed in patients with a history that warrants such investigation. A dose reduction of 50% is required for patients whose glomerular filtration rate has dropped less than 10 mL/min or if the patient is on dialysis.

How Supplied/Storage and Handling

Intravenous (IV) midazolam comes in 2 dosage forms: 1 mg/mL and 5 mg/mL. The investigators strongly suggest limiting the oral and maxillofacial surgery office stock to one dosage or the other to avoid medication errors. Most will choose the 1 mg/mL formulation that requires no dilution and facilitates ease of titration by the IV route. The oral form of midazolam comes in a 2 mg/mL concentration. Alternatively, the IV form can be mixed with juice to the appropriate dose and administered orally. These ampules are stored at room temperature.

Utility, Risks, and Benefits in Oral and Maxillofacial Surgical Practice

Midazolam has numerous benefits with minimal risks, making it an ideal medication for ambulatory anesthesia. These benefits include its sedative, amnestic, anxiolytic, central muscle relaxant, and anticonvulsant properties. Midazolam has modest dose-dependent hemodynamic and respiratory effects. Its innovative structure allows it to be packaged and administered as an aqueous solution that attains lipid solubility on entering the bloodstream. As such, the incidence of phlebitis/thrombophlebitis at the IV site is significantly lower than with diazepam, the benzodiazepine that was widely used in oral and maxillofacial surgery before the release of midazolam in the early 1980s.

Midazolam is an excellent agent for use in combination with an opioid such as fentanyl. A balanced anesthesia approach using these two drugs may reduce the dose requirement for each and may allow overlapping effects such as sedation to be enhanced synergistically while limiting drug-specific toxicities. In addition, the specific benefits of each of the agents, midazolam’s anxiolysis and amnesia and the analgesia and euphoria associated with fentanyl, are likely to combine well, producing a balanced and successful procedural sedation.

Among the significant benefits offered by midazolam is the availability of a specific reversal agent. Although the need for reversal is mitigated by the appropriate use of midazolam, particularly when carefully titrated via the IV route as described, the existence of flumazenil adds to the safety of midazolam and the clinician’s comfort with its use in the ambulatory setting.

Clinical Pharmacology

Fentanyl is a μ-opioid receptor agonist that inhibits the presynaptic release and postsynaptic response to excitatory neurotransmitters such as substance P and acetylcholine. IV fentanyl has roughly a 20- to 30-second onset of action with a duration of 20 to 30 minutes. It is rapidly metabolized to inactive end products in the liver by CYP3A4 through dealkylation and hydroxylation. Fentanyl is primarily eliminated in the urine, and approximately 10% undergoes biliary excretion.

Indications and Usage

Fentanyl is currently FDA approved for perioperative analgesia, as an adjunct to general or regional anesthetics, and for pain management.

Dosage and Administration

There are many different algorithms for which oral and maxillofacial surgeons can use fentanyl in a balanced anesthetic technique. At the author’s institution, an initial loading dose of fentanyl of 0.5 to 1 mcg/kg is given followed by incremental 25 mcg to 50 mcg boluses titrated to effect.

Contraindications

Contraindications for the use of fentanyl are generally only limited to patients with hypersensitivity.

Warnings and Precautions

Fentanyl, classified as a controlled substance II/IIN, can cause CNS depression, dose-dependent respiratory depression, cardiovascular depression, and serotonin syndrome. Individualized anesthetic plans should be devised for each patient. Clinical vigilance is required along with the application of all indicated monitoring devices so that the patient can be monitored throughout the procedure and until full recovery. An oxygen source, resuscitative medications, appropriate bag-valve-mask, and advanced airway equipment should be easily accessible in case an airway or cardiovascular event occurs.

Adverse Reactions

The most common adverse reactions include hypertension, hypotension, dizziness, blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm, anaphylaxis, respiratory depression, apnea, rigidity, and bradycardia. Chest wall rigidity is a feared complication of administration of fentanyl and is related to the dose and speed of administration. Cases of chest wall rigidity have even been reported with doses as little as 50 mcg intravenously.

Drug Interactions

Fentanyl should be avoided in patients who are taking medications that elevate serotonin levels, such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, and linezolid. Dose reduction should be considered in those taking CYP3A4 inhibitors. Use of fentanyl in patients who are taking serotonergic agents can lead to serotonin syndrome, with a range of symptoms including agitation, confusion, tachycardia, muscular twitching or rigidity, shivering, hyperpyrexia, dysrhythmias, and seizures. ^,

Use in Specific Populations

Fentanyl is a pregnancy category C drug; however, it is generally advisable to avoid elective procedures under anesthesia for pregnant patients. Historically, it has been recommended that breastfeeding patients pump and discard for 24 hours following anesthesia. However, several studies have shown clinically insignificant amounts of fentanyl in breast milk following its administration, suggesting that cessation of breastfeeding may be unwarranted. Nursing patients may resume breastfeeding in the postoperative period once they are awake and alert, as long as the administered dose of fentanyl is within recommended dosing parameters. The American Society of Anesthesiologists currently recommends lowering the dosage of or avoiding fentanyl in lactating patients; however, the American Society of Anesthesiologists does not recommend counseling patients to “pump and dump,” following administration of anesthesia.

When using in geriatric patients, doses of fentanyl should be decreased and titrated slowly while closely monitoring for respiratory and CNS depression.

For patients with renal impairment, dose adjustments are not needed until the glomerular filtration rate becomes less than 50 mL/min. For patients whose glomerular filtration rate (GFR) is 10 to 50 mL/min, doses should be decreased to approximately 75% of the typical dose. If the GFR drops to less than 10 mL/min, the dose should be decreased to 50% the usual dose.

The metabolism of a single dose of fentanyl is believed to be relatively unchanged in patients with liver failure. However, elimination is likely prolonged in patients with severe liver disease. As such, typical initial doses can be given, but caution should be exercised in administering repeat doses to prevent toxic accumulation.

How Supplied/Storage and Handling

Fentanyl is currently available only as a 50 mcg/mL solution in various ampule volumes including 2 mL, 5 mL, 10 mL, and 20 mL. These ampules are stored away from light and at room temperature.

Utility, Risks, and Benefits in Oral and Maxillofacial Surgical Practice

In addition to its anesthetic and analgesic properties, fentanyl offers a variety of advantages when used in the office-based ambulatory setting. When providing open airway anesthesia, as is commonly done in the practice of oral and maxillofacial surgery, fentanyl’s ability to blunt the cough reflex and attenuate a hyperactive airway may be of substantial value. Fentanyl also has the added benefit of being relatively inexpensive compared with other available opioids. Undesirable effects of fentanyl include an increase in incidence of postoperative nausea and vomiting (PONV). Liberal use of opioids should be avoided for patients with a reported history of prior postanesthetic nausea, motion sickness, and other known risk factors for PONV. Prophylactic measures to prevent this unpleasant complication such as fluid boluses and administration of IV dexamethasone or other antiemetic medications should be considered when planning to use fentanyl for at-risk patients. Risk assessment for PONV should be part of the preanesthetic workup for all patients being evaluated for ambulatory anesthesia.

As with midazolam, fentanyl has an effective and readily available reversal agent, naloxone. Naloxone should be used only when indicated, and in such cases, the patient should be monitored carefully for signs of renarcotization. When reversal becomes necessary during a balanced anesthesia technique with both midazolam and fentanyl, a quick but careful evaluation of the patient’s condition should lead to the correct choice of reversal agent. Both flumazenil and naloxone must be in the emergency kits of oral and maxillofacial surgeons who are using midazolam and fentanyl, and reversal protocols should be well known or readily accessible.

Clinical Pharmacology

Propofol is a rapidly acting IV medication commonly used for induction and maintenance of general anesthesia and sedation. Its onset from time of injection is approximately 40 seconds, due to rapid equilibration between the plasma and the brain. The half-time of blood brain equilibration is 1 to 3 minutes. Cardiorespiratory depression is likely to occur from bolus dosing or from a rapid increase in the rate of infusion of propofol. Generally, 3 to 5 minutes should be allowed between doses of propofol to adequately assess clinical effects. When propofol is dosed such that spontaneous ventilation is maintained, arterial hypotension may occur with little or no change in heart rate and no decrease in cardiac output. When propofol is dosed such that assisted or controlled ventilation is required, a decrease in cardiac output may occur. The reflex tachycardia seen with older induction agents such as methohexital is not a prominent feature of propofol and may not be seen at all. ^,

Propofol induction is frequently associated with apnea in all patient populations, which is exacerbated by the concurrent administration of opioid medications. Propofol is rarely associated with release of histamine and, on the contrary, may be associated with bronchodilation. It also does not reduce adrenal response to adrenocorticotropic hormone and is not a triggering agent for malignant hyperthermia. Following redistribution, propofol is cleared via hepatic conjugation into inactive metabolites and renally excreted. Rapid awakening within 10 to 15 minutes usually occurs when propofol has been used for a few hours or longer or even for extended periods at the minimum effective therapeutic concentration, as in an intensive care setting. When used at higher levels, propofol redistribution from fat and muscle to plasma may prolong recovery. Mild euphoria on awakening is common after propofol administration, and even at subhypnotic doses, propofol is associated with decreased postoperative nausea and vomiting. ^,

Indications and Usage

Propofol may be used as an induction and maintenance agent for general anesthesia in a variety of settings, including monitored anesthesia care, combined sedation and regional anesthesia such as for outpatient oral and maxillofacial surgery procedures, and for intensive care unit sedation of mechanically ventilated patients.

Dosage and Administration

The dosage and method of administration of propofol varies with the desired level of sedation and clinical purpose. Before drawing up the medication, the bottle should be shaken to achieve a uniform consistency. Notable phase separation indicates that the product is no longer stable. In adults, a 2 to 2.5 mg/kg bolus will induce general anesthesia within 30 seconds. Depending on the desired depth of anesthesia, periodic propofol bolus dosing may be used to maintain satisfactory anesthesia without overdosing. Changes in vital signs in response to surgical stimuli or a patient response indicating light anesthesia may be managed using propofol boluses of roughly 10 to 30 mg for sedation or 20 to 50 mg for general anesthesia. Concurrent inhalation of nitrous oxide and oxygen with propofol titration may achieve satisfactory anesthesia for minor procedures. A propofol infusion pump is also a useful tool for achieving and maintaining a desired anesthetic plane. FDA labeling recommends a rate of 50 to 100 mcg/kg/min for adults to optimize recovery time. This range may be expanded and broken down to 25 to 100 mcg/kg/min for moderate sedation, 75 to 150 mcg/kg/min for deep sedation, and 100 to 300 mcg/kg/min for general anesthesia. Infusion rates should be titrated down in the absence of clinical signs of light anesthesia. ^,

Contraindications

Propofol is contraindicated in patients with a known hypersensitivity to the drug itself or any of the preparation constituents. The FDA recommends that propofol be avoided in patients with true soy or egg allergies. However, most egg allergies are to the albumin in egg white and thus do not preclude the use of propofol emulsion, which specifically contains lecithin extracted from egg yolk. Several investigators have published reports indicating that concerns about the use of propofol in patients with the food allergies noted previously are unfounded. ^,

Warnings and Precautions

Propofol injection causes significant pain, which may be attenuated by pretreatment of the vessel with 1% lidocaine or by administering an opioid medication before propofol. If using lidocaine, the recommendation is no more than 20 mg per 200 mg propofol so that 1 or 2 mL of 1% plain lidocaine should suffice in advance of the first propofol bolus. Long-term sedation of critically ill children or young adult neurosurgical patients may result in propofol infusion syndrome, which is characterized by lipemia, rhabdomyolysis, hyperkalemia, metabolic acidosis, hepatomegaly, renal failure, electrocardiogram changes and/or cardiac failure, and death. This unusual syndrome is generally associated with high-dose infusion of propofol; decreased oxygen delivery to tissues; serious neurologic injury and/or sepsis; or the concurrent administration of high doses of steroids, vasoconstrictors, or inotropes. ^,

Adverse Reactions

Anaphylaxis, although rare, has been reported in patients with a history of allergic reaction to other medications, especially neuromuscular blocking agents.

Drug Interactions

Premedication with midazolam can reduce the propofol requirement by 10%. The respiratory effects of propofol, including reduced respiratory drive and its impact on cardiac output, are enhanced by opioid administration. ^,

Use in Specific Populations

Elderly, debilitated, and medically fragile patients are more susceptible to undesirable cardiorespiratory depression, so bolus dosing should be avoided or performed with great care in these populations. A reduced induction dose of 1 to 1.5 mg/kg is recommended for these patients, due to reduced clearance and higher blood concentrations. On the contrary, healthy pediatric patients aged 3 to 16 years require a higher induction dose of 2.5 to 3.5 mg/kg. Pediatric patients also require a correspondingly higher infusion rate for maintenance of general anesthesia, with younger pediatric patients requiring even higher rates than older pediatric patients. There are no adequate and well-controlled studies of propofol administration in pregnant women, and a pregnancy category has not been assigned, but animal studies have suggested adverse effects on the mother and/or the fetus when propofol is administered during pregnancy.

Pharmacokinetics of propofol in adult patients with chronic renal or hepatic impairment is no different from that of normal healthy adults.

How Supplied/Storage and Handling

Propofol is packaged as a 1% (10 mg/mL) aqueous solution consisting of soybean oil, glycerol, and egg lecithin that is opaque white. This formulation may support bacterial growth, so the vial is handled using sterile technique and must be used within 6 hours of opening. Although current preparations contain 0.005% disodium edetate or 0.025% metabisulfite as preservatives to slow the growth of microorganisms, this does not qualify as an antimicrobial preparation by US pharmacopeia standards. It is a schedule IV controlled substance. ^,

Utility, Risks, and Benefits in Oral and Maxillofacial Surgery/Ambulatory Anesthesia Practice

Propofol is usually titrated to effect to achieve, maintain, or deepen sedation during outpatient oral and maxillofacial surgery procedures. Typically, a benzodiazepine and an opioid medication will be given to achieve a baseline moderate sedation. Propofol is then administered in 10 to 30 mg bolus doses, usually during administration of local anesthesia or other stimulating portions of the surgical procedure. The oral and maxillofacial surgeon must be prepared to manage the respiratory consequences of propofol use including apnea during open airway sedation. For older clinicians who have experience with methohexital, the benefits of propofol are clear. Deep sedation with propofol is generally smoother, untoward reactions are fewer, recovery is quicker, and postoperative nausea is less likely than with methohexital.