Manual of Emergency Airway Management, 3rd Edition

18.Sedative Induction Agents

David A. Caro

Katren R Tyler

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.” Induction agents are among the most potent medications used in medicine today. The ideal agent would smoothly and quickly render the patient unconscious, unresponsive, and amnestic in one arm/heart/brain circulation time. Such an agent would also provide analgesia, maintain stable cerebral perfusion pressure and cardiovascular hemodynamics, be immediately reversible, and have few, if any, adverse side effects. Unfortunately, such an induction agent does not exist. Most induction agents meet the first criterion because they are highly lipophilic and, therefore, have a rapid onset within 15 to 30 seconds of intravenous (IV) administration. Their clinical effect is likewise terminated quickly as the drug rapidly redistributes to less well-perfused tissues. All induction agents have the potential to cause myocardial depression and subsequent hypotension. These effects depend on the particular drug; the patient's underlying physiological condition; and the dose, concentration, and speed of injection of the drug. The faster the drug is administered (intravenous [IV] push), the larger the concentration of drug that saturates those organs with the greatest blood flow (i.e., brain, heart) and the more pronounced the effect. Because RSI requires rapid administration of a preselected dose of the 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 induction agents include ultra–short-acting barbiturates: thiopental (Pentothal) and methohexital (Brevital); benzodiazepines: principally midazolam (Versed); and miscellaneous agents: etomidate (Amidate), ketamine (Ketalar), and propofol (Diprivan). Other agents, such as the opioid analgesic fentanyl (Sublimaze), can function as anesthetic induction agents when used in large doses (e.g., for fentanyl 30 µg/kg, 0.03 mg/kg); however, they are rarely, if ever, used for that purpose during emergency intubation, and so are not discussed here.

General anesthetic agents act via two principal mechanisms: (a) an increase in inhibition via GABA A receptors (e.g., benzodiazepines, barbiturates, propofol, isoflurane, etomidate, enflurane, halothane), and (b) a decreased excitation through NMDA receptors (e.g., ketamine, nitrous oxide, xenon).

The IV induction agents discussed in this chapter share important pharmacokinetic characteristics. As mentioned previously, they are highly lipophilic and, therefore, a standard induction dose of each in a euvolemic, normotensive patient will onset within 30 seconds. The observed clinical duration of each drug is measured in minutes and is due to the drugs' redistribution half-life (t1/2α) characterized by redistribution of the drug from the central circulation (brain) to larger, well-perfused tissues, such as fat and muscle. The elimination half-life (t1/2β, usually measured in hours) is characterized by each drug's re-entry from fat and lean muscle into plasma down a concentration gradient, followed by hepatic metabolism and renal excretion. Generally, it requires four to five elimination half-lives to clear the drug completely from the body.

Because the target organ is the brain, and the desired effect is produced rapidly following bolus injection of the drug, dosing of induction agents in non-obese adults should be based on ideal body weight in kilograms. This dosage can be estimated based on the patient's actual body weight, or a rough approximation can be obtained by subtracting 100 from the patient's height in centimeters; that is, 6 ft 4 inch = 76 inch × 2.54 cm/ inch = 193 cm – 100 = 93 kg. This approach provides an acceptable estimate of ideal body weight, and the administered induction dose can then be adjusted based on the clinical status of the patient. For obese patients, the situation is more complicated. The high lipophilicity of the induction agents and the increased volume of distribution (Vd) of these drugs in obesity would argue for total body weight dosing (see Chapter 35). Opposing this, however, is the significant cardiovascular depression that would occur if such a large quantity of drug was injected as a single bolus. Balancing these two considerations, and given the paucity of actual pharmacokinetic studies in obese patients, the best advice is probably to administer the induction agents according to lean body weight, where lean body weight is approximated by subtracting the ideal body weight from actual body weight and adding 30% of this difference to the ideal body weight. This is in contrast to succinylcholine, for which studies support dosing by total body weight in both adults and children. Further dosing guidelines are provided in Chapters 20 and 21 for pediatric patients and in Chapter 35 for morbidly obese patients.

Aging affects the pharmacokinetics of induction agents. In the elderly, lean body mass and total body water decrease while total body fat increases, resulting in an increased volume of distribution, an increase in t1/2β, and an increased duration of drug effect. In addition, the elderly ordinarily have decreased reserve and are much more sensitive to the hemodynamic and respiratory depressant effects of these agents, and consequently, most induction doses should be reduced, generally to approximately one half to three fourths of the dose used in their healthy, younger counterparts.

Ultrashort-acting Barbiturates

Usual Emergency Induction dose (mg/kg)

Onset (sec)

t1/2α (min)

Duration (min)

t1/2β (hr)

Thiopental (Pentothal)

3

<30

2–4

5–10

3–8

Methohexital (Brevital)

1.5

<30

5–6

5–10

2–5

A. Clinical Pharmacology

Thiopental is the prototypical barbiturate used for anesthetic induction. Methohexital is a close relative. Both are ultrashort-acting central nervous system (CNS) depressants that induce hypnosis (sleep) but not analgesia. Recovery after a small dose is rapid with some somnolence and retrograde amnesia. Repeated IV doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate thiopental in concentrations significantly greater than the plasma concentration, and then they release the drug slowly to cause prolonged anesthesia.

Methohexital is two to three times more potent than thiopental, 1.5 mg of methohexital being equal to 4 mg of thiopental. The t1/2β for methohexital is shorter than that for thiopental.

At low doses, ultrashort-acting barbiturates decrease GABA dissociation from its receptor, which enhances GABA's neuroinhibitory activity. At higher doses, they can directly stimulate the GABA receptor itself.

Barbiturates are cerebroprotective, causing a dose-dependent decrease in cerebral metabolic oxygen consumption and a parallel decrease in cerebral blood flow (CBF) and intracranial pressure (ICP), provided cerebral perfusion pressure is maintained.

Thiopental and methohexital are largely degraded in the liver. Neither have active metabolites.

B. Indications and Contraindications

Thiopental was widely used as a general purpose induction agent in the past, but it has largely been supplanted by etomidate and propofol. Its primary use now is as an induction agent for patients suspected of having increased ICP or status epilepticus because it has significant anticonvulsant activities in addition to the cerebroprotective properties outlined previously.

Thiopental releases histamine, and so is relatively contraindicated in patients with reactive airways disease.

Thiopental and all of the other barbiturates are absolutely contraindicated in patients with acute intermittent porphyria, or variegate porphyria, because they can activate the enzyme responsible for precipitating an acute attack, which can be life threatening.

Thiopental is classified by the U.S. Food and Drug Administration (FDA) as a pregnancy category C, primarily for risk of teratogenesis. Methohexital is an FDA pregnancy category B. Both readily cross the placenta and may cause respiratory depression in neonates.

C. Dosage and Clinical Use

The dosing of thiopental depends on the hemodynamic status of the patient and the concomitant use of other agents in RSI. Thiopental is a potent venodilator and myocardial depressant. Consequently, the dose must be decreased in patients with decreased intravascular volume, those with compromised myocardial function, the elderly, and whenever thiopental is used with other drugs that affect sympathetic tone or cardiovascular function. In euvolemic, normotensive adults, the recommended induction dose is 3 to 5 mg/kg IV. For most emergency intubations, the lower dose of this range, that is, 3 mg/kg, achieves excellent sedation and intubating conditions with less tendency to cause the hypotension that often occurs with the 5 mg/kg dose. The onset of methohexital is more rapid and the duration of action shorter than with thiopental. The recommended induction dose in the euvolemic, normotensive patient is 1.5 mg/kg IV.

In the adult patient who is suspected of hypovolemia, myocardial dysfunction, or compromised hemodynamic status, the dose of thiopental should be reduced to 1 to 2 mg/kg IV, and the dose of methohexital decreased to 0.5 to 1 mg/kg IV. Both should be avoided entirely in frankly hypotensive patients for whom other drugs, especially etomidate or ketamine, may preserve greater hemodynamic stability. With the widespread adoption of etomidate, which has significant cardiovascular stability, the ultra–short-acting barbiturates have seen limited use as induction agents for emergent RSI.

D. Adverse Effects

As with any induction agent, inadequate dosing leaves the patient more lightly sedated and makes laryngoscopy more difficult, even when neuromuscular blocking agents are used. The principal side effects of thiopental include central respiratory depression, venodilation, and myocardial depression. These latter two may be manifested by hypotension that tends to be greater in both treated and untreated hypertensive patients compared with normotensive patients. Both can be detrimental in many patients in whom optimal preload is required to maintain cardiac output and prevent organ ischemia. Barbiturates cause a dose-related release of histamine that in most situations is not clinically significant, but may cause or exacerbate bronchospasm in patients with reactive airways disease. Ketamine is the preferred induction agent for patients with reactive airways disease. Methohexital causes more excitatory phenomena (twitching, hiccups) than thiopental.

One to two percent of patients will experience pain on injection of thiopental, especially if small veins on the dorsum of the hand are used. Five percent of patients will experience pain on injection with methohexital. Inadvertent intra-arterial injection or subcutaneous extravasation of thiopental can result in chemical endarteritis and distal thrombosis, ischemia, and tissue necrosis due to its highly alkaline pH (>10). If extravasation occurs, 40 to 80 mg of papaverine (Cerespan) in 20 mL normal saline or 10 mL of 1% lidocaine (Xylocaine) should be injected intra-arterially proximal to the site to inhibit smooth muscle spasm. Consider local infiltration of an alpha-adrenergic blocking agent such as phentolamine into the vasospastic area.

Benzodiazepines

Usual Emergency Induction dose (mg/kg)

Onset (sec)

t1/2α (min)

Duration (min)

t1/2β (hr)

Midazolam (Versed)

0.2–0.3

60–90

7–15

15–30

2–6

A. Clinical Pharmacology

Although chemically distinct from the barbiturates, the benzodiazepines also exert their effects via the GABA-receptor complex. Benzodiazepines specifically stimulate the benzodiazepine receptor, which in turn modulates GABA, the primary neuroinhibitory transmitter. The benzodiazepines provide amnesia, anxiolysis, central muscle relaxation, sedation, anticonvulsant effects, and hypnosis. Although the benzodiazepines generally have similar pharmacological profiles, they differ in selectivity, which makes their clinical usefulness variable. The benzodiazepines have potent, dose-related amnestic properties, perhaps their greatest asset for emergency indications. The lipophilicity of the benzodiazepines varies widely. Greater lipid solubility confers a more rapid onset of action because of the brain's high lipid content. The three benzodiazepines of interest for emergency applications are midazolam (Versed), diazepam (Valium), and lorazepam (Ativan). Of the three, midazolam is the most lipid soluble and is the only benzodiazepine suitable for use as an induction agent for emergent RSI. That said, midazolam is virtually never used in correct induction doses for emergency intubations and is notoriously underdosed. Furthermore, the time to clinical effectiveness of benzodiazepines, in general, is longer than any of the other induction agents, further mitigating their role in emergent RSI. When IV midazolam is given as an anesthetic induction agent, induction of anesthesia occurs in approximately 1.5 minutes when narcotic premedication has been used and in 2 to 2.5 minutes without narcotic premedication. This slow onset of action is mitigated, to an extent, by the profound amnestic effects of midazolam, but its pharmacokinetic attributes make it a poor induction agent, and it cannot be recommended for this purpose. Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. The termination of action of midazolam is due to initial redistribution and subsequent hepatic metabolism via microsomal oxidation. Midazolam has one significant active metabolite, 1-hydroxy-midazolam, which may contribute to the net pharmacological activity of midazolam. Clearance of midazolam is reduced in association with old age, congestive heart failure, and liver disease. The elimination half-life of midazolam (t1/2β) may be prolonged in renal impairment. The benzodiazepines do not release histamine, and allergic reactions are very rare.

B. Indications and Contraindications

The primary indications for benzodiazepines are to promote amnesia and sedation. In this regard, the benzodiazepines are unparalleled. Midazolam's primary use in the emergency department and elsewhere in the hospital is for procedural sedation, lorazepam is used primarily for treatment of seizures and alcohol withdrawal, and these agents are used for sedation and anxiolysis in a variety of settings, including postintubation.

Because of their dose-related reduction in systemic vascular resistance and direct myocardial depression, dosage must be adjusted in volume-depleted or hemodynamically compromised patients. Studies have shown that induction doses of midazolam, 0.3 mg/kg, are rarely used, but, even at this dose, midazolam is a poor induction agent for emergency RSI.

All benzodiazepines are FDA pregnancy category D.

C. Dosage and Clinical Use

Although midazolam is used as an induction agent in the operating room, we do not recommend its use for emergency RSI. Even in the correct induction dose for hemodynamically stable patients of 0.2 to 0.3 mg/kg IV push, the onset is slow, and not suited to emergency applications. Midazolam should be reserved for sedative applications, and its use in emergency RSI is not advised because superior agents are readily available. Similarly, diazepam and lorazepam are not recommended for emergent RSI because of their slow onset of action.

D. Adverse Effects

Except for midazolam, the benzodiazepines are insoluble in water and are usually in solution in propylene glycol. Unless injected into a large vein, pain and venous irritation on injection can be significant.

Miscellaneous Agents

Etomidate (Amidate)

Usual Emergency Induction dose (mg/kg)

Onset (sec)

t1/2α (min)

Duration (min)

t1/2β (hr)

0.3

15–45

2–4

3–12

2–5

1. 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, inhibiting excitatory stimuli. Etomidate attenuates underlying elevated ICP by decreasing CBF and cerebral metabolic oxygen demand (CMRO2). Its hemodynamic stability preserves cerebral perfusion pressure. Etomidate may not be the most cerebroprotective of the various available induction agents (that attribute probably resides with the barbiturates), but 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 airways disease. However, it lacks the direct bronchodilatory properties of ketamine, which may be a preferable agent in these patients.

2. 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 cerebral perfusion pressure, and its rapid recovery. As with any induction agent, dosage should be adjusted in hemodynamically compromised patients. Etomidate is an FDA pregnancy category C.

Etomidate is not FDA approved for use in children, but many series report safe and effective use in pediatric patients (see Chapters 20 and 21).

3. Dosage and Clinical Use

In euvolemic and hemodynamically stable patients, the normal induction dose of etomidate is 0.3 mg/kg IV push. In compromised patients, the dose should be reduced commensurate with the patient's clinical status; reduction to 0.2 mg/kg is usually sufficient.

4. 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 agent takes effect.

The most significant and controversial side effect of etomidate is its reversible blockade of 11-beta-hydroxylase, which decreases both serum cortisol and aldosterone levels. This side effect has been more common with continuous infusions of etomidate in the intensive care unit setting rather than 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 (Ketalar)

Usual Emergency Induction dose (mg/kg)

Onset (sec)

t1/2α (min)

Duration (min)

t1/2β (hr)

1.5

45–60

11–17

10–20

2–3

1. 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 N-methyl-D-aspartate (NMDA) receptors at the GABA-receptor complex, promoting neuroinhibition and subsequent anesthesia. Action on opioid receptors accounts for its profound analgesic effect. Ketamine releases catecholamines, stimulates the sympathetic nervous system, and therefore augments heart rate and blood pressure in those patients who are not catecholamine depleted secondary to the demands of their underlying disease. Furthermore, increases in mean arterial pressure may offset any rise in ICP, resulting in a relatively stable cerebral perfusion pressure. This is discussed in detail in the Evidence section. In addition to its catecholamine-releasing effect, ketamine directly relaxes bronchial smooth muscle, producing bronchodilatation. Ketamine is primarily metabolized in the liver, producing one active metabolite, norketamine, which is metabolized and excreted in the urine.

2. Indications and Contraindications

Ketamine is the induction agent of choice for patients with reactive airways disease who require tracheal intubation. Because of its pharmacological profile, ketamine should also be considered the induction agent of choice for patients who are hypovolemic or hypotensive and for patients with hemodynamic instability due to 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 important in patients with significant hypotension, who are probably maximally catecholamine stimulated before the ketamine is given. 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. The pregnancy category of ketamine has not been established by the FDA.

3. Dosage and Clinical Use

The induction dose of ketamine for RSI is 1.5 mg/kg IV. In patients who are catecholamine depleted, doses greater than 1.5 mg/kg IV may cause myocardial depression, exacerbating hypotension. For sedation, ketamine is titrated to effect beginning with doses that approximate 10% of the calculated induction dose of the drug. Because of its generalized stimulating effects, ketamine enhances laryngeal reflexes and increases pharyngeal and bronchial secretions. These secretions may uncommonly precipitate laryngospasm and may be bothersome during upper airway examination during awake intubation, but are not an issue during RSI. Atropine 0.01 mg/kg IV or glycopyrrolate (Robinul) 0.01 mg/kg IV may be administered in conjunction with ketamine to promote a drying effect for awake intubation, although this is usually not necessary.

4. Adverse Effects

The hallucinations that occasionally occur on emergence from ketamine are more common in the adult than in the child and can be eliminated by the concomitant or subsequent administration of a benzodiazepine, if desired. This is rarely an issue in emergency airway management, in which the patient is usually sedated for prolonged periods, often with benzodiazepines.

Propofol (Diprivan)

Usual Emergency Induction dose (mg/kg)

Onset (sec)

t1/2α (min)

Duration (min)

t1/2β (hr)

1.5

15–45

1–3

5–10

1–3

1. Clinical Pharmacology

Propofol is an alkylphenol derivative (i.e., an alcohol) with hypnotic properties. It is highly lipid soluble. Propofol enhances GABA activity at the GABA-receptor complex. It decreases CMRO2 and ICP. Propofol does not cause histamine release. Propofol causes a direct reduction in blood pressure through vasodilatation and direct myocardial depression, resulting in a decrease in cerebral perfusion pressure, which may be detrimental to a compromised patient. The manufacturer recommends that rapid bolus dosing (either single or repeated) be avoided in patients who are elderly, debilitated, or ASA III/IV in order to minimize undesirable cardiovascular depression, including hypotension. It must be used cautiously for emergency RSI in hemodynamically unstable patients. It causes greater myocardial depression and venodilation than thiopental, when used in equivalent doses.

2. Indications and Contraindications

Propofol is an excellent induction agent in a stable patient. Its adverse potential for hypotension and reduction in cerebral perfusion pressure limits its role as an induction agent in emergent RSI. Propofol has been used as an induction agent during tracheal intubation for reactive airways disease. There are no absolute contraindications to the use of propofol. Propofol is delivered as an emulsion in soybean oil and lecithin. Patients who are allergic to eggs generally react to the ovalbumin and not to lecithin, and propofol is not contraindicated in patients with egg allergy. Propofol is a pregnancy category B drug.

3. Dosage and Clinical Use

The induction dose of propofol is 1.5 mg/kg IV in a euvolemic, normotensive patient. Because of its predictable tendency to reduce mean arterial blood pressure, smaller doses are generally used when propofol is given as an induction agent for emergency RSI in compromised patients.

4. Adverse Effects

Propofol causes pain on injection comparable to that of methohexital, less than etomidate, and more than thiopental. This effect can be attenuated by injecting the medication through a rapidly running IV in a large vein (e.g., antecubital). Premedication with lidocaine (2–3 mL of 1% lidocaine) will also minimize the pain of injection. Propofol and lidocaine are compatible in the same syringe and can be mixed in a 10:1 ratio (10 mL of propofol to 1 mL of 1% lidocaine). Propofol can cause mild clonus to a greater degree than thiopental, but less than etomidate or methohexital. Venous thrombophlebitis at the injection site can sometimes occur.

Evidence

1. What is the correct dosing of midazolam for RSI? The dose of midazolam for induction of anesthesia is 0.2 to 0.3 mg/kg IV. The data to support this dose are from dosing studies conducted in the 1980s after the introduction of midazolam into clinical practice (1,2,3,4,5,6,7,8,9). Interestingly, Sagarin et al. (10), as a substudy of the National Emergency Airway Registry (NEAR) project, recently demonstrated that most emergency intubations performed with midazolam generally use doses in the 0.03 to 0.04 mg/kg range, dramatically less than the minimum recommended induction dose. Their analysis showed that this is likely due to inexperience with the larger doses of midazolam used for induction (10). In any case, midazolam is a poor choice as an induction agent for emergency RSI because of its relatively slow onset.

2. Which induction agents are most hemodynamically stable? Etomidate results in the least variation in blood pressure and heart rate when compared to the other agents used for rapid induction of anesthesia (11,12,13,14,15). Etomidate also appears to have less effect on cardiac function as determined by echocardiographic findings (15). This effect is seen in children and adults, including the elderly (11,14).

3. Should etomidate be used in sepsis syndrome? Etomidate has been widely adopted as the agent of choice for the induction phase of RSI because of its superior hemodynamic stability, reliable and predictable effects, rapidity of onset, brief duration of action, and lack of serious side effects (16).

A single dose of etomidate will produce transient adrenal suppression through blockade of 11 β-hydroxylase, with suppression lasting up to 24 hours and perhaps beyond (17,18). Within the past 5 years, increased attention has focused on adrenal insufficiency in sepsis, the role of corticosteroids to treat these patients, and whether the use of etomidate as an induction agent constitutes an unnecessary risk (19,20). Although no studies to date have measured outcomes when sepsis patients were randomized to etomidate versus other agents, this has not deterred some authors from recommending proscription of the use of etomidate in sepsis. The most assertive of these has been published as a letter (21) and personal communication (22) in response to a report of a clinical trial involving low-dose corticosteroids in patients with septic shock (23). Annane et al. (23) reported 72 patients with septic shock received etomidate, of whom 68 subsequently failed to respond to corticotropin stimulation. A post hoc subgroup analysis of these 68 nonresponders revealed higher mortality rates in patients who had been randomized to receive placebo versus corticosteroids (76% vs. 55%) (22). The meaning of this finding is not clear. More recently, Lipiner-Friedman et al. (24), in a retrospective multicenter study on the use of corticosteroids in sepsis, concluded that etomidate influenced ACTH test results and was associated with a worse outcome. This study excluded etomidate use within 24 hours prior to the start of the study. Two hundred and thirty-seven (50%) patients received at least one dose of etomidate more than 24 hours before the study started. By their analysis, etomidate use was associated with a moderately increased risk of dying (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.06–2.26). However, the use of vasopressors was associated with a markedly increased risk of dying (OR 38.52; 95% CI 20.69–71.73) (24). These findings underscore the limitations of retrospective study designs and the weakness of post-hoc analysis, in which patients were not randomized with respect to the agent being studied (in this case, etomidate). It is difficult to determine, after the fact, whether the etomidate had some real adverse effect, or whether the observed outcomes were the result of other factors. For example, it is difficult to accept that the use of vasopressors caused a 38-fold increase in mortality, and no one is calling for a moratorium on their use. Opposing the move against etomidate, a study by Riché et al. (25), also retrospective, compared septic shock patients who underwent general anesthesia with or without etomidate and found no adverse effect on survival. In this study, response to a corticotrophin stimulation test did not predict survival (25). Another recent study compared the use of etomidate and other induction agents in 159 patients with septic shock and found that vasopressor therapy was required less frequently and in smaller doses when etomidate was used to induce anesthesia (18). However, this study is also subject to the same inability to control for confounders.

Etomidate has superior hemodynamic characteristics and offers, along with ketamine, the best opportunity to avoid postintubation hypotension. For this reason, etomidate has emerged as the induction agent of choice for emergency intubation of patients with hemodynamic instability or shock (26). Until more specific data are available, it would be premature to subject critically ill septic shock patients to worsened hypotension on the basis of a loosely inferred association drawn from retrospectively reanalyzed data.

Three approaches might be considered for the use of etomidate in patients with septic shock:

a. Eliminate etomidate use altogether in these patients. Although a few passionate advocates of this approach have emerged, principally in the critical care community, there is no evidence to support it. As summarized previously, there are no well-designed studies demonstrating that etomidate is detrimental to patients in septic shock. Although ketamine is also a reasonable agent for these hemodynamically compromised patients (27,28,29,30,31), etomidate is widely used and familiar with a wide margin of safety.

b. Routinely administer corticosteroids to septic shock patients who have received etomidate (32). Advocates of this approach argue that the administration of corticosteroids might correct adrenal suppression, if any, caused by etomidate (16,32). Again, although there are theoretical reasons why this might make sense, there is no evidence to support this approach; therefore, it cannot be recommended.

c. Inform subsequent care providers that etomidate was used during intubation, so that they can consider this in their care of the patient. In the presence of existing evidence, this would seem the appropriate approach.

4. Is ketamine use acceptable in patients with elevated ICP? Ketamine has not been recommended for patients with elevated ICP for more than three decades after early, small studies apparently showed increased cerebral oxygen consumption, CBF, and ICP after ketamine administration in these patients. Recently, evidence has emerged that has cast doubt on these longheld beliefs (33,34,35,36,37,38,39). Of most interest to those performing emergency intubation, the cerebral hemodynamic effects of ketamine are not as detrimental as previously believed. In spontaneously breathing volunteers, ketamine increases CBF and cerebral metabolism. In patients undergoing controlled ventilation and sedation, however, ketamine does not appear to increase ICP. When ketamine is used for sedation and analgesia in intubated head injured patients, the cerebral perfusion pressure is stable when compared with opioid/benzodiazepine combinations, mean arterial pressure is maintained, and vasopressor use is decreased (36,37,38,39).

It has been repeatedly shown that systemic hypotension is harmful in brain injury. Systolic blood pressure of 90 mm Hg or less in the emergency department is the single risk factor most highly associated with mortality in severe blunt head injury (35). Any mechanism by which hypotension can be avoided in traumatic brain injury should be encouraged. Ketamine maintains mean arterial pressure and has been shown not to increase ICP in ventilated patients. Ketamine should be considered for use in the multiply injured patient with head injury who is hypotensive on induction (39). A similar argument could be extended to medical causes of elevated ICP (tumor, hemorrhage.) In these patients, too, it would seem prudent to use an alternative agent when the blood pressure is normal or high, but ketamine is reasonable to consider when hypotension is present.

5. What is the best induction agent in patients with seizures? Etomidate has been shown to increase activity in certain electroencephalogram (EEG) leads in comparison to other sedatives when given to patients induced for general anesthesia. Thiopental, propofol, and midazolam all suppress EEG activity more quickly and completely than etomidate (40). Propofol, midazolam, or thiopental is a logical choice for RSI in the status seizure patient, followed by an infusion in the postintubation phase and ongoing EEG monitoring. Use of etomidate in the patient with status seizure is not contraindicated, but there are clearly superior agents for this indication (see Chapter 33).

6. What is the best induction agent for patients with severe bronchospasm? Ketamine and propofol both cause bronchodilation when used for induction (41,42,43,44,45). Eames et al. (43) prospectively demonstrated that 2.5 mg/kg of propofol was superior to either 0.4 mg/kg etomidate or 5 mg/kg thiopental in decreasing mean airway pressure during bronchoscopy in 75 patients. Simon, et al. (44) demonstrated immediate improvement after propofol in 6 of 18 intubated patients with severe asthma on ventilators, compared to 8 of 13 who were placed on halothane anesthesia. Hemmingsen, et al. (45) demonstrated a clinically and statistically significant improvement in respiratory dynamics after prospectively infusing ketamine or placebo to 14 asthmatics on ventilators. Etomidate causes a mild increase in airway resistance, but thiopental causes a significant rise in bronchospasm and resistance (43,46). Midazolam data are lacking. Ketamine is the recommended drug for patients without known coronary artery disease because it is readily available, can be given IV push, and results in an increase in hemodynamic parameters such as heart rate and blood pressure, in contrast to propofol.

7. What is the role of the induction agent in intubation success? The choice of sedative used for intubation may influence intubation success rates, especially if lower doses of a paralytic agent are used. A retrospective analysis of the NEAR data suggests that thiopental, methohexital, and propofol have higher first attempt intubation success rates compared to etomidate, benzodiazepines, ketamine, or no induction agent (47). Skinner, et al. (48) found that propofol was better than etomidate; however, Fuchs-Buder, et al. (49) found no difference between thiopental and etomidate with rocuronium paralysis. Hans et al. found ketamine superior to Pentothal, when rocuronium 0.6 mg/kg was the paralytic (50). El-Orbany et al. (51,52) found no difference between thiopental, propofol, and etomidate when rapacuronium was used as the paralytic agent. Although there is no clear winner, these variations underscore the importance of the induction agent to RSI success. Even though neuromuscular blockade is used, the dose and selection of the induction agent influence success, probably because of additive relaxation at the early phase of neuromuscular paralysis at which intubation is first attempted. Correct dosing of both the neuromuscular blocking agent and the sedative agent are required to achieve optimal intubating conditions during RSI.

8. In the obese patient, how should I dose the induction agent? This is discussed in Chapter 35.

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