ANESTHETIC AGENTS

A number of diverse drugs are routinely used in the ED to induce anesthesia prior to intubation. These include thiopental, methohexital, ketamine, etomidate, and propofol. Midazolam and fentanyl may also be used; these two agents are more commonly used at low doses as conscious sedation agents (see Analgesia and Sedation). The choice of a particular anesthetic agent depends to a great extent on the experience and training of the physician and to a

TABLE 3-1 -- Rapid-Sequence Induction Protocol
1.	Preoxygenate (denitrogenize) the lungs by providing 100% oxygen by mask. If ventilatory assistance is necessary, bag gently while applying cricoid pressure.
2	Assemble required equipment: Bag-valve-mask connected to an oxygen delivery system Suction with Yankauer tip Endotracheal tube with intact cuff, stylette, syringe, tape Laryngoscope and blades, in working order Cricothyrotomy tray
3.	Check to be sure that a functioning, secure IV line is in place.
4.	Continuously monitor the cardiac rhythm and oxygen saturation.
5.	Premedicate as appropriate: Fentanyl: 2 to 3 mug/kg given at a rate of 1 to 2 mug/kg/min IV for analgesia in awake patients Atropine: 0.01 mg/kg IV push for children or adolescents (minimum dose of 0.1 mg recommended) Lidocaine: 1.5 to 2.0 mg/kg IV over 30 to 60 seconds
6.	. Induce anesthesia with one of the following agents administered intravenously: thiopental, methohexital, fentanyl, ketamine, etomidate, or propofol.
7.	Give succinylcholine 1.5 mg/kg IV push (use 2.0 mg/kg for infants and small children).
8.	Apnea, jaw relaxation, and decreased resistance to bag/mask ventilations indicate that the patient is sufficiently relaxed to proceed with intubation.
9.	Perform endotracheal intubation. If unable to intubate during the first 20-second attempt, stop and ventilate the patient with the bag-mask for 30 to 60 seconds. Follow pulse oxymetry readings as a guide.
10.	Treat bradycardia occurring during intubation with atropine 0.5 mg IV push (smaller dose for children; see item 5).
11.	Once intubation is completed, inflate the cuff and confirm endotracheal tube placement by auscultating for bilateral breath sounds and checking pulse oxymetry and capnography readings.
12.	Release cricoid pressure and secure endotracheal tube.

certain extent on institutional protocols governing use of these agents. Drugs commonly used and their doses are listed in Table 3-2 .

Barbiturates: Thiopental and Methohexital

The barbiturates, in particular thiopental, have been the traditional agents used for RSI in the operating room. These agents are used less often in the ED setting because of their

TABLE 3-2 -- Recommended Anesthetic Doses for Rapid-Sequence Induction
Drug *	Dose
Thiopental	3-5 mg/kg IV
Methohexital	1-3 mg/kg IV
Fentanyl	5-15 mug/kg IV
Ketamine	1-2 mg/kg IV
Etomidate	0.3 mg/kg IV
Propofol	2.0 mg/kg IV

reputation as cardiorespiratory depressants. Of these two agents, methohexital is used more commonly in the ED because of its extremely rapid onset and short duration of action.

Pharmacology
Following IV injection,the ultrashort-acting barbiturates bind rapidly to plasma proteins, particularly albumin. Unbound barbiturate quickly accumulates in highly vascular organs, reaching peak brain levels in as short a time as 50 seconds. The drugs then diffuse from the brain, ultimately reaching equilibrium between the intracerebral and plasma concentrations. Degradation occurs primarily in the liver, producing inactive metabolites that are excreted in the urine or gut, depending on the drug used. Single-pass hepatic clearance is substantially higher for methohexital than for thiopental, which accounts for the former drug's shorter duration of action. The period of anesthesia following a single IV dose of methohexital is 4 to 6 minutes, compared with 5 to 10 minutes for thiopental. [13] [14]

The barbiturates are central nervous system (CNS) depressants that are capable of producing mild sedation to deep coma. They do not block afferent sensory impulses to a significant extent and therefore should be used in conjunction with an analgesic agent such as fentanyl if a painful procedure is to be performed. However, it is common practice to intubate patients who have received only barbiturates. [14]

The advantages of barbiturates as adjuncts to intubation include their high potency, rapid onset, and short duration of action, traits they share with fentanyl and midazolam. The barbiturates are also known to reduce cerebral metabolism and oxygen consumption and, secondarily, cerebral blood flow and intracranial pressure (ICP). [15] [16] For this reason, thiopental is considered the agent of choice for anesthesia induction and maintenance in patients with elevated ICP. Some have stated that thiopental is the drug of choice to temporarily anesthetize the patient with a head injury before intubation. It has not been proved, however, that barbiturates exert a protective effect on the CNS when used for a short period of time during RSI. Moreover, their use in trauma patients may lead to systemic hypotension and impaired cerebral perfusion pressure that may offset the theoretic advantages of barbiturate therapy.

Dose
The recommended doseof thiopental is 3 to 5 mg/kg IV administered as a 2.5% solution over 60 seconds. Normal saline should be used as a diluent. Methohexital is given at 1 to 3 mg/kg IV over 30 to 60 seconds.

Adverse Effects
It has been stated that barbiturates are "fatally easy" to use. [14] This is an overstatement that reflects improper use of the drugs more than an inherent danger associated with their proper use. The most significant complication of barbiturate therapy is depression of the vasomotor center and myocardial contractility leading to significant hypotension. This may be particularly pronounced in the presence of hypovolemia or cardiovascular disease.

Barbiturates also depress the brainstem respiratory centers when given rapidly or in large doses. This effect may be accelerated by simultaneous treatment with opioids. Patients

with asthma or chronic bronchitis may experience bronchospasm. Laryngospasm may occur in patients who were anesthetized lightly with barbiturates during manipulation of the upper airway. Laryngospasm usually responds to positive-pressure ventilation or paralysis with succinylcholine. In addition, the high pH of the barbiturate solution can cause tissue necrosis following extravascular administration and severe pain, vessel spasm, and thrombosis following intraarterial infusion.

Etomidate
Etomidate is an ultrashort-acting nonbarbiturate hypnotic agent that has been used successfully as an anesthesia induction agent in Europe since the mid-1970s and in the United States since 1983. Only recently has it been used as an adjunct to intubation in the ED. A potentially significant benefit of etomidate in the emergency setting is its lack of cardiodepressant effects. [17] Although experience in this setting is limited, etomidate's potency, rapid onset, short duration of action, and minimal side effects suggest that it will become much more widely used.

Pharmacology
Etomidate is a carboxylated imidazole that is both water and lipid soluble. The drug rapidly accumulates in vascular organs, reaching peak brain concentrations within 1 minute of IV infusion. [18] Sleep is produced within 1 arm-brain circulation time and lasts less than 10 minutes following a single bolus infusion. [19] Redistribution of the drug is quite rapid (distribution half-life, 2.6 minutes), which accounts for the short duration of action. Etomidate is rapidly hydrolyzed in the liver and plasma, forming an inactive metabolite excreted primarily in the urine. [18]

Etomidate acts on the CNS to stimulate gamma-aminobutyric acid receptors and depress the reticular activating system. After IV infusion, etomidate produces electroencephalographic changes similar to those produced by barbiturates as patients pass rapidly through light to deep levels of surgical anesthesia. Because etomidate has no analgesic activity, [18] it should be used in conjunction with an analgesic such as fentanyl when painful conditions are being treated. Etomidate decreases cerebral oxygen consumption, cerebral blood flow, and ICP but appears to have minimal effects on cerebral perfusion pressure. [20]

Dose
The recommended dose is 0.3 mg/kg IV.There is virtually no accumulation of the drug, and anesthesia may be maintained through repeated or continuous dosing. [21]

Adverse Effects
The most common side effectsof etomidate are nausea and vomiting, pain on injection, and myoclonic jerks. [22] Pain on injection occurs in up to two thirds of cases. Use of a large vein, simultaneous saline infusion, and opioid premedication are reported to reduce this side effect. [23] Myoclonic activity has been reported in about one third of cases and is believed to be caused by disinhibition of subcortical activity rather than CNS stimulation. [18]

Ketamine
Pharmacology
Unique among anesthetic agents currently in use, ketamine produces a dissociative anesthesia characterized by excellent analgesia and amnesia despite the appearance of wakefulness. As a drug that is potent and relatively safe and possesses a rapid onset and brief duration of action, ketamine fits the profile of a drug that could be used effectively to facilitate intubation. It does, however, possess a number of pharmacologic properties that limit its use to selected circumstances.

Ketamine is a water- and lipid-soluble drug with rapid penetration into the CNS. Like the barbiturates, ketamine accumulates rapidly in highly vascular organs and then undergoes redistribution. The half-life of redistribution from plasma to peripheral tissues is 7 to 11 minutes, and the half-life of elimination is 2 to 3 hours. Degradation occurs primarily in the liver. [24]

Unlike other anesthetic agents that depress the reticular activating system, ketamine acts by interrupting association pathways between the thalamocortical and limbic systems. Characteristically, the eyes remain open, and patients exhibit spontaneous, although not purposeful, movements. Increases in blood pressure, heart rate, cardiac output, and myocardial oxygen consumption are seen--effects that are most likely mediated through the CNS. In vitro studies indicate that ketamine is a myocardial depressant, but the CNS-mediated pressor effects generally mask the direct cardiac effects. [25] [26] Respirations are initially rapid and shallow after ketamine administration, but they soon return to normal.

Other features of ketamine anesthesia include increased skeletal muscle tone, preservation of laryngeal and pharyngeal reflexes, hypersalivation, and relaxation of bronchial smooth muscle. ICP is increased, most likely as a consequence of increased cerebral blood flow. [24]

Ketamine has been recommended for anesthesia induction in children because of its relative safety and infrequency of postanesthesia emergence reactions in this group. There is no evidence, however, that it offers any advantage over commonly used agents. Ketamine also has been recommended for the unstable critically ill patient, because it does not depress the cardiovascular system. This recommendation is too vague to be useful to the clinician, and it ignores the fact that ketamine is potentially harmful in patients with cardiac ischemia (because it can increase myocardial oxygen consumption) or acute intracranial pathology (because it can increase ICP). Ketamine may be useful during hemorrhagic shock because of its cardiostimulatory effect. Its administration to patients in shock has been reported to cause a fall in blood pressure only when the shock state has been prolonged. [29] [30]

The most promising use of ketamine as an intubation adjunct has been in the setting of acute bronchospastic disease. Ketamine relaxes bronchial smooth muscle either directly, through the enhancement of sympathomimetic effects, or through the inhibition of vagal effects. Ketamine also increases bronchial secretions, which may decrease the incidence of mucus plugging commonly reported in autopsies of asthmatic patients. [31] Clinical studies have demonstrated a reduction in airway resistance and an increase in pulmonary compliance that occur within minutes of ketamine administration. L'Hommedieu and Arens [8] reported

prompt improvement in respiratory acidosis in 5 asthmatics intubated with ketamine and succinylcholine.

Dose
The recommended dose of ketamine before intubation is 1 to 2 mg/kg administered IV over 1 minute. Anesthesia occurs within 1 minute of completing the infusion and lasts approximately 5 minutes. A small dose (0.5 to 1.0 mg/kg) may be given 5 minutes after the initial dose if there is a need to maintain anesthesia. The simultaneous administration of succinylcholine and midazolam is recommended to provide adequate muscle relaxation and to decrease the incidence of postanesthesia emergence reactions.

Adverse Effects
A side effect that has greatly limited the use of ketamine is its tendency to produce postanesthesia emergence reactions, a characteristic that it has in common with the structurally similar drug phencyclidine. The reactions may be marked and distressing to the patient; symptoms include floating sensations, dizziness, blurred vision, out-of-body experiences, and vivid dreams or nightmares. The reported incidence of these reactions varies from 5 to 30%. They are less common in children than in adults.

Of the drugs that have been evaluated for their ability to suppress postanesthesia emergence reactions, the benzodiazepines show the most promise. Both diazepam and lorazepam are useful, but the latter is more effective, most likely owing to its enhanced amnestic effect. Midazolam has not been evaluated as thoroughly as have the other benzodiazepines, but it has potent amnestic effects and offers the advantage of a short duration of action. White [40] reported a 55% incidence of postemergence dreaming in patients receiving ketamine and complete suppression of dreaming with the addition of midazolam. Evidence also suggests that midazolam may inhibit the cardiostimulatory effects of ketamine.

Although ketamine produces excellent analgesia and is relatively safe, its use as an agent to facilitate intubation is somewhat limited. The widely held belief that aspiration does not occur with ketamine because of preservation of pharyngeal and laryngeal reflexes is incorrect. Moreover, ketamine does not relax skeletal muscle. The production of desired intubation conditions often requires the simultaneous administration of a paralytic agent, thereby removing any upper airway reflexes.

Propofol
Emergency department experience with propofol is limited, and it is uncertain whether it will have a significant role as an adjunct to intubation in this setting.

Pharmacology
Propofol is an alkylphenol sedative-hypnotic recently introduced for induction and maintenance of general anesthesia. The drug has no analgesic activity, but it does have an amnestic effect. It produces dose-dependent depression of consciousness ranging from light sedation to coma. Propofol is a highly lipophilic, water-insoluble compound that undergoes rapid uptake by vascular tissues, including the brain, followed soon afterward by redistribution to the muscle and fat. The drug is metabolized by the liver and excreted in the urine.

Dose
Following an induction dose of 2 mg/kg IV, hypnosis occurs within 1 minute and lasts for 5 to 10 minutes. A smaller dose (1.0 to 1.5 mg/kg) is recommended in the elderly and when simultaneously administering other CNS depressants. Because propofol has a short duration of action and patients rapidly regain consciousness, repeat bolusing is not a practical way to maintain a desired level of anesthesia or sedation. A slow drip infusion of 3 to 5 mg/kg/hour titrated to effect is the preferred technique. Conscious sedation may be achieved using a drip infusion beginning at 6 mg/kg/hour and decreasing the rate as the desired level of sedation is obtained.

Adverse Effects
Side effects of propofol include direct myocardial depression causing a moderate fall in blood pressure, particularly in the elderly, in hypovolemic patients, and when administered simultaneously with opioids. Propofol reduces cerebral blood flow and may cause mild CNS excitation activity (e.g., myoclonus, tremors, hiccups) during anesthesia induction. Pain on injection occurs commonly, even when the drug is infused slowly.