Sedative Induction Agents

INTRODUCTION

Agents used to sedate, or “induce,” patients for intubation during rapid sequence intubation (RSI) are properly called sedative induction agents because induction of general anesthesia is at the extreme of the spectrum of their sedative actions. In this chapter, we refer to this family of drugs as “induction agents.” The ideal induction agent would smoothly and quickly render the patient unconscious, unresponsive, and amnestic in one arm/heart/brain circulation time. It would also provide analgesia, maintain stable cerebral perfusion pressure (CPP) and cardiovascular hemodynamics, be immediately reversible, and have few, if any, adverse physiologic effects. Unfortunately, such an induction agent does not exist. Most induction agents meet the first criterion because they are highly lipophilic and so have a rapid onset within 15 to 30 seconds of intravenous (IV) administration. Their clinical effects are also terminated quickly as the drug rapidly redistributes to less well-perfused tissues. However, all induction agents have the potential to cause myocardial depression and subsequent hypotension. These effects depend on the particular drug; the patient’s underlying physiologic condition; and the dose, concentration, and speed of injection of the drug. The faster the drug is administered IV, the larger the concentration of drug that saturates organs with the greatest blood flow (i.e., brain and heart) and the more pronounced its effect. Because RSI requires rapid administration of a precalculated dose of an induction agent, the choice of drug and the dose must be individualized to capitalize on desired effects, while minimizing those that might adversely affect the patient. Some patients are so unstable that the primary goal is to produce amnesia rather than anesthesia because to produce the latter might lead to severe hypotension and organ hypoperfusion.

The most commonly used emergency induction agent is etomidate (Amidate), which is popular because of its rapid onset of action, relative hemodynamic stability, and widespread availability. Recent registry data suggest ketamine (Ketalar) and propofol (Diprivan) are the next two most commonly used induction agents, but both trail far behind etomidate. Midazolam is still used as an induction agent but should be considered a distant fourth option and only used if other agents are unavailable. It is less reliable in inducing anesthesia, has a slower onset of action, and is more likely to produce hypotension than either etomidate or ketamine. The ultra–short-acting barbiturates such as methohexital (Brevital) and the ultra–short-acting narcotics such as sufentanil are rare in the ED and will not be discussed in further detail in this chapter. Additionally, thiopental is no longer available in North America and is rarely used in other countries. The relatively selective α₂-adrenergic agonist dexmedetomidine is not used as an RSI induction agent because it is not administered as a rapid bolus by IV push.

General anesthetic agents act through two principal mechanisms: (1) an increase in inhibition through activity at gamma-aminobutyric acid “A” (GABA) receptors (e.g., benzodiazepines, barbiturates, propofol, etomidate, isoflurane, enflurane, and halothane), and (2) a decreased excitation through N-methyl-D-aspartate (NMDA) receptors (e.g., ketamine, nitrous oxide, and xenon).

The IV induction agents discussed in this chapter share important pharmacokinetic characteristics. Induction agents are highly lipophilic and because the brain is a highly perfused, lipid-dense organ, a standard induction dose of each agent (with the exception of midazolam) in a euvolemic, normotensive patient will produce unconsciousness within 30 seconds. The blood–brain barrier is freely permeable to medications used to induce anesthesia. The observed clinical duration of each drug is measured in minutes because of the drugs’ distribution half-life (t_1/2a), characterized by distribution of the drug from the central circulation to well-perfused tissues, such as brain. The redistribution of the drug from brain to fat and muscle terminates its central nervous system (CNS) effects. The elimination half-life (t_1/2β, usually measured in hours) is characterized by each drug’s reentry from fat and lean muscle into plasma down a concentration gradient leading to hepatic metabolism and renal excretion. Generally, it requires four to five elimination half-lives to completely clear the drug from the body.

The dosing of induction agents in nonobese adults should be based on ideal body weight (IBW) in kilograms; however, in clinical practice, the total body weight (TBW or actual body weight) is a close enough approximation to IBW for the purposes of dosing these agents. The situation is more complicated for morbidly obese patients, however. The high lipophilicity of the induction agents combined with the increased volume of distribution (V_d) of these drugs in obesity argues for actual body weight dosing. Opposing this, however, is the significant cardiovascular depression that would occur if such a large quantity of drug is injected as a single bolus. Balancing these two considerations, and given the paucity of actual pharmacokinetic studies in obese patients, the best approach is to use lean body weight (LBW) for dosing of most induction agents, decreasing to IBW if the patient is hemodynamically compromised, or for drugs with significant hemodynamic depression, such as propofol. LBW is obtained by adding 0.3 of the patient’s excess weight (TBW minus IBW) to the IBW, and using the sum as the dosing weight. More details on drug dosing for obese patients is discussed in Chapter 40.

Aging affects the pharmacokinetics of induction agents. In elderly patients, lean body mass and total body water decrease while total body fat increases, resulting in an increased volume of distribution, an increase in t_1/2_β, and an increased duration of drug effect. In addition, the elderly are more sensitive to the hemodynamic and respiratory depressant effects of these agents, and the induction doses should be reduced to approximately one-half to two-thirds of the dose used in their healthy, younger counterparts.

ETOMIDATE

Etomidate (Amidate)
Usual emergency induction dose (mg/kg)	Onset (s)	t_1/2α (min)	Duration (min)	t_1/2β (h)
0.3	15–45	2–4	3–12	2–5

Clinical Pharmacology

Etomidate is an imidazole derivative that is primarily a hypnotic and has no analgesic activity. With the exception of ketamine, etomidate is the most hemodynamically stable of the currently available induction agents. It exerts its effect by enhancing GABA activity at the GABA–receptor complex. GABA receptors moderate the activity of inhibitory chloride channels, thus making neurons less excitable. Etomidate attenuates the underlying elevated intracranial pressure (ICP) by decreasing cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO₂). Its hemodynamic stability preserves CPP. Etomidate is cerebroprotective (although not as much as other agents like the barbiturates); its hemodynamic stability and favorable CNS effects make it an excellent choice for patients with elevated ICP.

Etomidate does not release histamine and is safe for use in patients with reactive airway disease. However, it lacks the direct bronchodilatory properties of ketamine or propofol, which may be preferable agents in these patients.

Indications and Contraindications

Etomidate has become the induction agent of choice for most emergent RSIs because of its rapid onset, its hemodynamic stability, its positive effect on CMRO₂ and CPP, and its rapid recovery. As with any induction agent, dosage should be adjusted in hemodynamically compromised patients. Etomidate is a U.S. Food and Drug Administration (FDA) pregnancy category C drug.

Etomidate is not FDA approved for use in children, but many series report safe and effective use in pediatric patients.

Dosage and Clinical Use

In euvolemic and hemodynamically stable patients, the normal induction dose of etomidate is 0.3 mg per kg IV push. In compromised patients, the dose should be reduced commensurate with the patient’s clinical status; reduction to 0.2 mg per kg is usually sufficient. In morbidly obese patients, the induction dose should be based on LBW, by using IBW, and adding a correction of 30% of the excess weight (see earlier).

Adverse Effects

Pain on injection is common because of the diluent (propylene glycol) and can be somewhat mitigated by having a fast-flowing IV solution running in a large vein. Myoclonic movement during induction is common and has been confused with seizure activity. It is of no clinical consequence and generally terminates promptly as the neuromuscular blocking (NMB) agent takes effect.

The most significant and controversial side effect of etomidate is its reversible inhibition of adrenal cortisol production by blockade of 11-β-hydroxylase, which decreases both serum cortisol and aldosterone levels. This side effect occurs both with continuous infusions of etomidate in the ICU setting and with a single-dose injection used for emergency RSI. The risks and benefits of the use of etomidate in patients with sepsis are discussed in detail in the “Evidence” section at the end of the chapter.

KETAMINE

Ketamine (Ketalar)
Usual emergency induction dose (mg/kg)	Onset (s)	t_1/2α (min)	Duration (min)	t_1/₂β (h)
1.5	45–60	11–17	10–20	2–3

Clinical Pharmacology

Ketamine is a phencyclidine derivative that provides significant analgesia, anesthesia, and amnesia, with minimal effect on respiratory drive. The amnestic effect is not as pronounced as that seen with the benzodiazepines. Ketamine is believed to interact with the NMDA receptors at the GABA–receptor complex, promoting neuroinhibition and subsequent anesthesia. Action on opioid receptors accounts for its analgesic effect. Ketamine stimulates the release of catecholamines, activating the sympathetic nervous system, and augmenting heart rate and blood pressure (BP) in those patients who are not catecholamine depleted secondary to the demands of their underlying disease. Furthermore, increases in mean arterial pressure (MAP) may offset any rise in ICP, resulting in a relatively stable CPP. In addition to its catecholamine-releasing effect, ketamine directly relaxes bronchial smooth muscle, producing bronchodilation. Ketamine is primarily metabolized in the liver, producing one active metabolite, norketamine, which is metabolized and excreted in the urine.

Indications and Contraindications

Ketamine is the induction agent of choice for patients with reactive airway disease who require tracheal intubation, and is also an excellent induction agent for patients who are hypovolemic, hypotensive, or hemodynamically unstable, including those with sepsis. In normotensive or hypertensive patients with ischemic heart disease, catecholamine release may adversely increase myocardial oxygen demand, but it is unlikely that this effect is detrimental in patients with significant hypotension, in whom additional catecholamine release may support the BP. Ketamine’s preservation of upper airway reflexes makes it appealing for awake laryngoscopy and intubation in the difficult airway patient where the dose is titrated to effect. Concern has been raised regarding ketamine’s effect on ICP, especially in the head-injured patient. Although it has been linked to mild increases in ICP, ketamine also increases MAP and therefore CPP. Ketamine has been increasingly used in head-injured patients, and no study to date has identified an increase in mortality when used in the head-injured patient. The pregnancy category of ketamine has not been established by the FDA, and so it is currently not recommended for use in pregnant women.

Dosage and Clinical Use

The induction dose of ketamine for RSI is 1.5 mg per kg IV. In patients who are catecholamine depleted, doses more than 1.5 mg per kg IV may cause myocardial depression and exacerbate hypotension. Because of its generalized stimulating effects, ketamine enhances laryngeal reflexes and can increase pharyngeal and bronchial secretions. These effects may uncommonly precipitate laryngospasm, and may interfere with upper airway examination during awake intubation, but are generally not an issue during RSI. Atropine 0.01 mg per kg IV or glycopyrrolate (Robinul) 0.005 mg per kg IV may be administered 15 minutes before ketamine to promote a drying effect for awake intubation, when feasible. Ketamine is available in three separate concentrations: 10, 50, and 100 mg per mL. Care should be taken to verify which concentration is utilized during RSI to avoid inadvertent over- or underdosing.

Adverse Effects

Hallucinations may occur on emergence from ketamine and are more common in adults than in children. Such emergence reactions occur infrequently in the emergency department as most patients are subsequently sedated with either a benzodiazepine or propofol, after the airway has been secured.

PROPOFOL