Chapter 9

Intravenous Induction Agents

A complete discussion of the pharmacology of the barbiturates is available in the 4th edition of this textbook.

An historic milestone in anesthesia was reached in 2011 with the decision to cease marketing sodium pentothal, a thiobarbiturate, in the United States and many other countries. Thiobarbiturates, when they were introduced in the 1930s, changed the way anesthesia was delivered. Although their use has declined dramatically in recent decades with the introduction of propofol, the practice of using intravenous push boluses of sedatives to initiate anesthesia remains the standard. Induction refers to the start of anesthesia when the patient is rendered unconscious. The intravenous induction agents allow the patient to experience a pleasant loss of consciousness while also rapidly achieving surgical levels of anesthesia.

A single ideal intravenous anesthesia induction drug has yet to be developed; however, the agents currently available can be exploited to select an appropriate drug for all surgical and anesthetic requirements. Desirable properties for an induction agent include rapid and smooth onset and recovery, analgesia, minimal cardiac and respiratory depression, antiemetic actions, bronchodilation, lack of toxicity or histamine release, and advantageous pharmacokinetics and pharmaceutics. Propofol is the current standard agent and is widely used for induction of general anesthesia and intravenous sedation. Etomidate and ketamine are valuable agents for select anesthetics when propofol use is undesirable. Dexmedetomidine is gaining popularity for niche uses as well. This chapter discusses the advantages and limitations of the currently used intravenous anesthesia induction agents.

Nonbarbiturate Intravenous Anesthetics

Propofol

Chemical Structure and Pharmaceutics

Propofol is a 2, 6-diisopropyl phenol (Figure 9-1). It is prepared as a 1% solution in a lipid emulsion of 10% soybean oil, 2.25% glycerol, and 1.2% purified egg lecithin. The pH of propofol (Diprivan) is 7 to 8.5, and the pK_a (negative logarithm of the acid ionization constant) is 11. The pH of the generic form of propofol is 4.5 to 6.4, and the pK_a is 11.¹ This unique vehicle is especially favorable to bacterial contamination. The original trade product, Diprivan, contains 0.005% disodium edetate (EDTA [ethylenediamine tetraacetic acid]) as a preservative to inhibit bacterial and fungal growth. Generic forms of propofol contain 0.025% sodium metabisulfite or benzyl alcohol depending on the manufacturer. Clusters of infections reported after mishandling of earlier preservative-free preparations prompted the addition of these preservatives.² Careful handling is still important. It is recommended that aseptic conditions be maintained and the drug be used immediately upon withdrawal from a vial for a single patient. Any remaining drug should be discarded. Syringes or vials should never be used for more than one patient. Opened vials or syringes should be discarded within 12 hours or 6 hours if propofol was transferred from the original container.

FIGURE 9-1 Agents used for the induction of general anesthesia, sedation, and benzodiazepine reversal.

The pharmaceutical preparations are shown in Table 9-1.

TABLE 9-1

Pharmaceutic Preparation of Intravenous Anesthetic Agents

EDTA, Disodium ethylenediamine tetraacetic acid.

^∗0, None; +, mild; ++, moderate; +++, marked.

Reformulations of Propofol

Newer formulations of propofol are being investigated that will have a more favorable vehicle than the lipid emulsion. These include other soybean and albumin emulsions, micelles and nanoemulsion cyclodextrins among others.1,3

A clear aqueous preparation of propofol as a phosphate prodrug is available for conscious sedation. A prodrug is a drug administered in an inactive or significantly less active form. Once administered, the prodrug is metabolized in the body into the active compound. Although propofol has many advantages such as rapid onset and offset when given for minor procedures such as colonoscopy or bronchoscopy, it can also present some challenges. It has a narrow therapeutic index, and hemodynamic and respiratory depression as well as general anesthesia can easily result from minor dose adjustments. Unlike the benzodiazepines, there is no pharmacologic antagonist. Fospropofol (Lusedra®) is being marketed as a safer formulation for mild to moderate sedation.⁴ As a prodrug it requires metabolic conversion to active propofol. The resulting slow onset makes it unsuitable for general anesthetic induction. The aqueous preparation avoids the injection pain associated with lipid emulsions. Figure 9-2 depicts the conversion of the prodrug of propofol by plasma alkaline phosphatases to the active propofol molecule, releasing formaldehyde and phosphate. Formaldehyde is further metabolized to formate by formaldehyde dehydrogenase. Select pharmacokinetic and clinical properties of fospropofol are listed in Box 9-1.^4–6

BOX 9-1 Clinical Pharmacology for Fospropofol (Lusedra)

Indication

Intravenous sedation in adults undergoing diagnostic or therapeutic procedures

Dose and Administration

• Standard dose: Initial dose 6.5 mg/kg

• Supplemental dose: 1.6 mg/kg no more frequently than every 4 minutes

• For patients 65 years old or younger and without severe systemic disease: Standard doses apply

• For patients 65 or more years old or with severe systemic disease: Modified dose 75% of standard dose

Pharmacokinetic Profile Compared to Propofol

• Onset: 5-13 minutes

• Duration: 15-45 minutes (depending on dose)

• Volume of distribution (L/kg): Fospropofol: 0.3; propofol: 5.8

• Total body clearance (L/hr/kg): Fospropofol: 0.36; propofol: 3.2

• Terminal elimination half-life (hours): Fospropofol: 0.88; propofol: 1.13

Most Frequent Adverse Events (Incidence 5% or greater)

Perineal paresthesia, pruritus, hypoxemia, hypotension

FIGURE 9-2 Conversion of the prodrug of propofol to the active propofol molecule by alkaline phosphatases.

Pharmacokinetics

Propofol exhibits a generally favorable kinetic profile, which is one of its main clinical benefits in comparison with other induction drugs (Table 9-2).^7,8 Rapid distribution following an IV (intravenous) bolus dose into the brain and other highly perfused areas results in a fast onset of generally one circulation time. Rapid redistribution from the central to the peripheral compartments as the drug more evenly distributes to the entire body produces a quick initial decline in blood levels. As distribution continues, the drug is circulated to less well perfused tissues such as muscle, and the brain concentration falls. This effect leads to a rapid reawakening after sedative and anesthetic doses. The time to awakening is dose and patient dependent but is usually in the range of 5 to 15 minutes. The movement of propofol through various body compartments over time is depicted in Figure 9-3. A visual conceptualization of the redistribution of drugs given by rapid push bolus is shown in Figure 9-4.

TABLE 9-2

Select Pharmacokinetic Values for Intravenous Anesthetic Agents

FIGURE 9-3 Propofol kinetics. Note that propofol rapidly enters the brain and other vital organs, with peak effects at 1 minute after bolus injection. The brain concentration then falls rapidly over the next 10 to 15 minutes as the drug redistributes more evenly throughout the body to muscle and fat.

FIGURE 9-4 Redistribution of intravenous drugs is shown. A and B, A drug is administered in the arm and follows the venous circulation to the heart. C, The high cardiac output and circulatory flow initially distribute the drug to the brain and upper body, and rapid central nervous system effects begin. D, E, and F, As time passes, usually minutes, the drug more evenly distributes throughout the body, lowering the initial high brain concentration, and the patient awakens.

Metabolism plays little role in the initial awakening of the patient but is important in the eventual clearance of the drug. An interesting characteristic of propofol is its rapid metabolic clearance, which actually exceeds hepatic blood flow.⁸ These extra hepatic sites of metabolism probably account for the lack of changes in elimination seen in patients with severe cirrhosis. ⁹ Less than 1% of propofol is excreted unchanged. It is rapidly metabolized in the liver by CYP2B6, UGTHP4, and CYP2C6.¹⁰ The drug’s kinetics are also influenced by age, with the elderly requiring lower doses.¹¹ Children require higher doses because they have an increased volume of distribution based on body weight. Their rate of clearance is also higher.¹² Some accumulation can occur with prolonged infusion secondary to tissue saturation.¹³ The elimination half-life is 1 to 2 hours.

Concerns that the traditional concept of half-life is misleading when drugs are given for prolonged periods by infusion led to the introduction of context-sensitive half time. The context is the duration of the infusion.¹⁴ It is the time required for a 50% decrease in plasma concentration after an infusion. Further refinements have described decrement times that include the 20% and 80% declines.¹⁵ The decrement time is from the end of the infusion to 50% recovery and includes pharmacokinetic data related to concentration decrease and pharmacodynamic data correlating with recovery. These concepts are discussed in Chapter 6.

Propofol reversibly binds to erythrocytes (50%) and plasma proteins, most commonly to plasma albumin (48%). The free concentration is less than 2%.¹⁶ Decreased plasma protein levels resulting from severe renal or hepatic disease and those patients in the third trimester of pregnancy may lower drug binding and increase the free active fraction. This may increase the effects of propofol. Clinically this may be a factor when prolonged infusions are used.¹⁷ Factors that can alter protein binding are noted in Table 9-3. Drugs that are highly lipid soluble cross cell membranes rapidly, including the blood-brain and placental barriers. Propofol being highly soluble easily enters all body compartments.¹⁸

TABLE 9-3

Factors That Alter Protein Binding

Factors	Percent Bound
Decreased lipid solubility	Decreases binding
Increased pH (≤8.0)	Increases binding
Increased drug concentration	Decreases binding
Increased protein concentration	Increases binding
Increased competition for binding sites with other drugs	Decreases binding

Mechanism of Action

Like many other sedatives and anesthetics, propofol appears to exert its effect via an interaction with the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the GABA_A glycoprotein receptor complex.¹⁹ γ-Aminobutyric acid (GABA) is a major inhibitory transmitter in the central nervous system (CNS). The GABA_A receptor, which is a ligand-gated ion channel receptor, is activated by the binding of the neurotransmitter GABA. This binding of GABA to the GABA_A receptor initiates the movement of chloride (Cl⁻) through ion channels into the cell. This results in hyperpolarization of postsynaptic cell membrane and the inhibition of neuronal cell excitation. A model has been developed that includes sites of action for GABA on the postsynaptic membrane, as well as sites for numerous other drugs. Propofol directly stimulates GABA_A receptors and potentiates the actions of endogenous GABA. The GABA receptor and its function are described in Figure 9-5.

FIGURE 9-5 The GABA_A receptor. A, The generic GABA_A receptor subunit has four hydrophobic transmembrane segments that are thought to form amphipathic α-helices. The N-terminal domain contains N-glycosylation sites and a conserved cysteine bridge; it forms the agonist-binding site. The large intracellular loop undergoes phosphorylation in several isoforms. B, Plane view of the transmembrane hydrophobic segments showing interactions to form a central ion-conducting pore lined by the second transmembrane domains. The hetero-oligomeric structure consists of five subunits, with each subunit contributing to the ion channel pore. C, The GABA_A receptor gates an anion channel permeable to Cl⁻ and HCO₃⁻. The general anesthetics are distinguished from the benzodiazepines (which allosterically modulate GABA binding to potentiate GABA responses) by their ability to activate/gate the GABA_A receptor channel directly. A separate site at the interface between the third and fourth transmembrane segments appears to interact with volatile anesthetics, alcohols, and etomidate, as demonstrated by site-directed mutagenesis studies. (From Hemmings HC, Hopkins PM, (eds): Foundations of Anesthesia Basic and Clinical Sciences, 2nd ed. St Louis: Mosby; 2006.)

Pharmacodynamics

Central Nervous System Effects

Propofol produces a rapid and pleasant loss of consciousness and emergence from anesthesia. Low-dose infusions for conscious sedation result in dose-dependent anxiolysis, sedation, and amnesia.²⁰ There are dose-dependent reductions in cerebral blood flow (CBF), cerebral metabolic rate of oxygen consumption (CMRO₂), intracranial pressure (ICP), and cerebral perfusion pressure(CPP).²¹ These effects result in part from the decreased mean arterial pressure, depressed metabolic rate, and cerebral vasoconstriction produced by standard doses in a manner comparable to the effects of barbiturates and etomidate.^22,23 Cerebral autoregulation and reactivity to changes in carbon dioxide (CO₂) are preserved with propofol. Hyperventilation should be applied cautiously in patients with an increase in ICP to avoid hypocarbia-induced cerebral circulatory compromise.²⁴

Electroencephalogram (EEG) data produced a delta rhythm without evidence of epileptiform activity and burst suppression with higher doses.²⁵ Even with these findings, controversy exists over the use of propofol in the patient with epilepsy.²⁶ Three epileptic patients were reported to experience increased epileptiform activity on EEG after the administration of propofol 2 mg/kg.²⁷ Studies in patients with epilepsy showed a different response in that the EEG showed no increase in epileptogenic activity at any of the sites monitored.²⁸ It was also found that activation or extension of EEG activity was greater with thiopental than with propofol (although not statistically significant).²⁹ Propofol has been used successfully to manage status epilepticus.³⁰ Myoclonia induced by propofol results in spontaneous excitatory movements secondary to selective disinhibition of subcortical centers. Adequate dosage may prevent the occurrence of these movements. Myoclonia may occur on induction, but the incidence appears to be lower than that with etomidate. Opisthotonos has also been associated with propofol. Intraocular pressure is decreased by propofol.³¹ Evidence for a neuroprotective effect is controversial because studies in both animals and humans have not been consistent. Propofol cannot be indicated as a clinical neuroprotectant alone, but it might play an important role in multimodal neuroprotection. Beneficial effects include preservation of cerebral perfusion, temperature control, prevention of infections, and tight glycemic control.³²

The use of propofol for electroconvulsive therapy (ECT) has been somewhat controversial as a result of the drug’s effects on seizure duration. Several studies have shown that propofol reduces the duration of the ECT-induced seizure when compared with barbiturates. Evaluating the efficacy of ECT as an antidepressant was typically based on the duration of the seizure; a shortened seizure implied a less effective therapy. However, researchers have found that a reduction in seizure duration does not decrease the efficacy of the ECT, and that propofol is an appropriate agent for use in this procedure.33–35

CNS effects of the intravenous induction drugs are shown in Table 9-4.

TABLE 9-4

Central Nervous System Effects of Intravenous Anesthetics

CBF, Cerebral blood flow; CPP, cerebral perfusion pressure; CMRO₂, cerebral metabolic rate of oxygen consumption; ICP, intracranial pressure; IOP, intraocular pressure.

↓, Decreases; ↑, increases; 0, no effect.

Cardiovascular Effects

Propofol usually results in a mild to moderate transient decrease in blood pressure in healthy adults and children during anesthesia induction. The decrease in blood pressure is not usually clinically significant. The effects are more pronounced than those seen with equivalent doses of etomidate or midazolam. It can, however, result in significant hypotension in usual induction doses in select patients. Predictors of hypotension during induction are age greater than 50 years, ASA (American Society of Anesthesiologists) class 3 to 4, baseline mean arterial pressure less than 70 mmHg, and coadministration of high doses of fentanyl. Hypotension usually occurs within 10 minutes after induction and is more prevalent in the second half of the 0- to10-minute interval.³⁶ As with most cardiovascular-depressing sedatives, these effects result from varying degrees of a combination of CNS, cardiac and baroreceptor depression, and decreases in sympathetic tone and systemic vasodilation. The primary reasons for propofol-induced hypotension are decreased sympathetic tone and vasodilation.³⁷ Central nervous system and direct cardiac depression play less of a role. A decrease in dose or alternative agents should be considered in the elderly or cardiac-compromised patients. Propofol has been used successfully for cardiac anesthesia when combined with fentanyl in low-dose or infusion regimens (Table 9-5).³⁸

TABLE 9-5

Cardiac and Respiratory Effects of Intravenous Anesthetic Agents

−, Mild decrease; − −, moderate decrease; +, mild increase; ++, moderate increase; 0, no effect.

Respiratory Effects

Transient respiratory depression, more prominent than that seen with etomidate, is common with induction doses of propofol. Decreases in tidal volume are greater than decreases in respiratory rate, although apnea is common on initial administration of induction doses.³⁹ The frequency and duration of apnea are dependent on the dose, speed of injection, patient characteristics, and the presence of other respiratory depressant medications.⁴⁰ Dose-dependent respiratory depression is also common with maintenance infusions. This appears to result from a decreased sensitivity of the respiratory center to carbon dioxide.⁴¹

Propofol has a minimal bronchodilating effect in patients with or without asthma and in patients who smoke. It does not cause histamine release and has been used successfully for anesthesia induction in asthmatic patients. After tracheal intubation, respiratory resistance is lower, and the incidence of wheezing is decreased, compared with the effects of etomidate.42,43 Propofol or ketamine are the preferred induction agents in patients with asthma.⁴⁴

Other Pharmacologic Actions

Propofol possesses mild antiemetic effects that are most prominent when given by continuous infusion.45,46 The mechanism for the antiemetic effects is unclear. It also exhibits antipruritic effects against opioid-induced pruritus.^47,48

Patients experience mild to moderate pain on injection with propofol. The incidence is approximately 60% and is most frequently related to the use of smaller veins for injection The two most effective interventions to reduce pain on injection are the use of the antecubital vein or pretreatment with lidocaine 20 to 40 mg in conjunction with venous occlusion when the hand vein was chosen. Other effective pretreatments are using a lidocaine-propofol admixture, opioids, ketamine, and nonsteroidal antiinflammatory drugs.⁴⁹ Intraarterial injection of propofol does not cause vascular injury.

Obstetric Use

As you would expect from a highly lipid soluble drug, propofol easily passes the placental barrier when administered to a pregnant woman. Sedative effects occur in the neonate when propofol is used for cesarean delivery. Lower 1- and 5-minute Apgar scores have been noted.⁵⁰

The anti-emetic effects of propofol may be an advantage in these patients. It is also used for sedation and hypnosis in postpartum tubal ligations and assistive reproductive techniques.

Contraindications and Precautions

Few absolute contraindications exist for propofol other than cases in which a known hypersensitivity exists to propofol or its components or the patient has a disorder of lipid metabolism.51,52 New generic formulations of propofol, which contain sodium metabisulfite, should not be used in sensitive patients. The sulfite may cause allergic-type reactions such as anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulfite sensitivity is more common in patients with asthma than in patients without asthma.⁵³ As noted, caution is advised in elderly, debilitated, and cardiac-compromised patients.

Allergy

Propofol lipid emulsion formulations have been scrutinized because of their lecithin content. Lecithin (from the Greek lekithos, meaning “egg yolk”) is a phospholipid compound composed of a range of phosphatidyl esters such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. These are combined with varying amounts of triglycerides and fatty acids. Lecithin was originally obtained from eggs, although now soybeans and other vegetables with high lecithin content have also become useful sources. Apart from its use as an antioxidant synergist, lecithin has important surfactant properties and is used as an emulsifying agent.⁵⁴

Controversy exists regarding whether propofol should be avoided in patients who are allergic to eggs, soy, or peanuts. Egg allergy is most common in children and usually outgrown by adulthood.⁵⁵ The 2009 guidelines published by the Association of Anesthetists of Great Britain and Ireland claim there is no evidence that propofol should be avoided in egg- or soy-allergic patients.^56,57 The warning labels differ among countries for the same formulation of propofol supplied by the same company. The product information for Diprivan 1% warns of its use in egg- or soy-allergic individuals in Australia, soy/peanut (but not egg) in the United Kingdom, and lists no food allergy warnings in the United States. This is despite all three formulations being supplied by the same company.⁵⁶

A retrospective case review of 28 egg-allergic patients was recently reported. Two of the 28 patients had documented egg anaphylaxis. All but the two children with a history of egg anaphylaxis safely received propofol.⁵⁸ Data on the two children with documented egg anaphylaxis were not conclusive. The authors suggest propofol is likely to be safe in most egg-allergic children; however, propofol should not be administered to any child with a history of egg anaphylaxis until further evidence is available. Other authors note that there are no confirmed reports of propofol-induced anaphylaxis in egg-allergic patients. They generally demonstrate immediate hypersensitivity to proteins from egg whites. Lecithin is from egg yolks, so there is no reason to contraindicate propofol in egg-allergic patients.⁵⁹

Soy allergy is a common early onset food allergy in children. Many children outgrow the allergy by age 7.⁶⁰ Refined soy oil of the types used in propofol have the allergenic proteins removed during refining; therefore it is safe in patients with soy allergy. The suggestion that peanut-allergic patients may exhibit propofol allergy is due to cross reactivity between these leguminous plants; therefore just as with soy allergy, there are also no data to support the avoidance of propofol in patients with peanut allergy.⁵⁹

Propofol Infusion Syndrome

Propofol is frequently used in adult and pediatric intensive care units for prolonged sedation. Numerous case reports, however, describe findings of various metabolic derangements and organ system failures known collectively as propofol infusion syndrome (PRIS) with long-term high-dose infusions of propofol.⁶¹ This has not occurred in anesthesia, even with prolonged administration of relatively high doses, because it seems to require long-duration infusions of increasing doses, as only encountered in critical care units.⁶² This syndrome is associated with significant morbidity and mortality. A precise mechanism of action of PRIS has yet to be demonstrated.⁶³ Risk factors include young age, doses greater than 4 to 5 mg/kg/hr, duration greater than 48 hours, critical illness, high-fat low-carbohydrate intake, inborn errors of mitochondrial fatty acid oxidation, concomitant catecholamine infusion, and steroid administration. Many of the patients who developed this syndrome have been children, but several cases in adults have been identified as well.

The syndrome has occurred in patients with acute inflammatory disease with infection or sepsis or acute neurologic disease. One common denominator was the presence of impaired systemic microcirculation with tissue hypoperfusion and hypoxia. Propofol seemed to be a triggering agent when catecholamines and corticosteroids are also administered. Fatty acid metabolism and mitochondrial activity are impaired, creating an oxygen supply-and-demand mismatch that results in cardiac and peripheral muscle necrosis. The current theory proposes that propofol inhibits oxidative phosphorylation by (1) inhibition of the transportation of long-chain fatty acids into the cell as well as (2) inhibitory effects on the mitochondrial respiratory chain. Symptoms include severe metabolic acidosis, refractory cardiac failure, persistent bradycardia refractory to treatment, fever, and severe hepatic and renal disturbances.⁶⁴ The clinical features are noted in Box 9-2. Treatment is supportive and includes discontinuing the propofol, improving gas exchange, cardiac pacing for bradycardia, phosphodiesterase inhibitors, glucagon, extracorporeal membrane oxygenation, and renal replacement therapy.⁶³

BOX 9-2 Clinical Features of Propofol Infusion Syndrome

Cardiovascular

• Hypotension

• Widening of the QRS complex

• Bradycardia

• Ventricular tachycardia or fibrillation

• Asystole

Respiratory

• Hypoxia (preexisting)

Renal

• Acute kidney injury

• Hypertriglyceridemia

• Lipidemia

Key points regarding propofol are listed in Box 9-3. Induction doses of the intravenous anesthetics are shown in Table 9-6.

BOX 9-3 Key Points for Propofol Anesthesia

• Propofol is the most commonly used intravenous anesthetic as an induction drug and for sedation.

• Respiratory effects include transient respiratory depression or apnea, depending on dose. Although not a bronchodilator, safe use in asthmatics has been well established.

• Propofol is unique among induction agents in that it exhibits mild antiemetic properties.

• Propofol has a rapid onset and emergence after bolus or continuous infusions of the drug.

• Patients emerge with a mild euphoria followed by rapid dissipation of the sedative effects.

• Propofol reduces cerebral blood flow, CMRO₂, and ICP.

• Propofol decreases blood pressure, cardiac output, and systemic vascular resistance to a greater extent than etomidate at equipotent doses.

• The induction dose is 1-2 mg/kg followed by a maintenance infusion of 100-200 mcg/kg/min. Conscious sedation doses are 25-75 mcg/kg/min.

CMRO₂, Cerebral metabolic rate of oxygen consumption; ICP, intracranial pressure.

TABLE 9-6

Induction Doses of the Intravenous Anesthetics