KETAMINE, like many other drugs, was the fruit of investigative labors shared by anesthesiologists and pharmacologists, as recently described by Domino1in an excellent account of the early years of development and use of this drug. Ketamine was first administered to humans in 1964, and results of that early experience were published in 1965.2Now on its way to boasting a 50-yr history of clinical utility, ketamine is a candidate for membership in the select club of classic drugs still in good standing, alongside aspirin, morphine, lidocaine, and diazepam. In its mechanism of action, ketamine differs from conventional inhalation and injection anesthetics mainly because it is a noncompetitive antagonist at the N -methyl-D-aspartate receptor.3 

“The findings of Eikermann [and coworkers], that ketamine can be used in spontaneous ventilation and that the airway remains unobstructed, confirm that this anesthetic merits our confidence in its safety profile.”

Figure. No caption available.

Figure. No caption available.

Early on, clinicians noted the beneficial effects of ketamine on the respiratory system, observing that central respiratory drive depression was scant; upper airway muscle, pharyngeal, and laryngeal reflexes were preserved; and there was an evident bronchodilator effect. These novel features were surprising, distinguishing a ketamine-induced clinical state from that of other general anesthetics or opioids, as well as from a state of coma. When Corssen and Domino4recruited healthy volunteers for a 1965 study of the effects of ketamine on the parameters of breathing, they recorded a slight transient decrease in minute volume but maintenance of arterial blood gases. The words of these authors are worth reading today:

Of particular interest was the observation that protective reflexes—pharyngeal, laryngeal, eyelid, and corneal—were present during the entire course of anesthesia. During surgery inside and around the mouth, there was no need for an endotracheal tube…. In some instances the jaw muscles appeared to be more tense.

In this issue of ANESTHESIOLOGY, Eikermann et al .5contribute to our understanding of the respiratory effects of ketamine on the basis of two carefully conceived, elegant experiments in rats. In the first, they compared the acute effects of administering ketamine and propofol, taking measurements at the median effective dose (ED50) and after administration of doses that were 0.66 of the ED50and 1.5-fold the ED50. In the second experiment, the authors used chronically instrumented rats (carrying electrodes for genioglossus and neck electromyography, as well as for the recording of a cortical electroencephalogram) to study effects in four situations: in awake and sleep states and after low and high doses of ketamine injected intraperitoneally. Their results confirm that ventilatory depression is scant, and that there is a slight increase in the duty cycle (inspiratory time divided by total respiratory cycle time). However, the most remarkable findings they report are that ketamine increases genioglossus muscle activity while abolishing the coupling between loss of consciousness and upper airway dilator muscle activity. These results can be extrapolated to humans only cautiously, given that the airway effects of anesthetics differ between species. The contraction of the large genioglossus muscle elevates the tongue and pushes it forward, increasing the diameter of the upper airway and decreasing its collapsibility.6,7Hypotonia causes posterior displacement to a position where the tongue may occlude the pharynx. Thus, electromyography of the genioglossus muscle has been considered an important indication of upper airway patency.

In the decades that have passed between the publication of the article by Corssen and Domino4and this most recent contribution based on animals, we have seen few studies of the upper airway muscle effects of ketamine. In cats, Nishino et al .8demonstrated in the 1980s that ketamine activates the adductor muscles to open the larynx. Authors from the same laboratory also showed that although thiopental and diazepam depress hypoglossal nerve activity more than phrenic nerve activity, ketamine affects these nerves similarly.9Thus, ketamine better preserves upper airway patency and muscle activity. Later, Drummond10compared the effects of midazolam and ketamine by placing electrodes on the tongue and neck of human subjects, finding that intravenous ketamine (1 mg/kg) did not cause a significant decrease in tongue muscle activity, in contrast with a 42% decrease observed after injection of midazolam (5 mg). More recently Saponjic et al .11injected ketamine into the pedunculopontine tegmental nucleus of rats, observing patterns that suggest that respiratory rate and muscle tone seem to be glutamate-mediated processes at the N -methyl-D-aspartate receptors.

However, maintenance of pharyngeal muscle tone and upper airway patency are no guarantee against bronchial aspiration. Most reviews emphasize that ketamine preserves reflexes in the pharynx and larynx, but little research has been done to confirm this. Carson et al .12studied laryngeal function indirectly by first instilling a radiopaque contrast medium into the pharynx and then looking for radiographic evidence of aspiration into the tracheobronchial tree after sedation with ketamine and other drugs with or without premedication in obstetric patients. They reported that aspiration to the lung was slight after low doses of ketamine (1 mg/kg) in nonpremedicated patients. However, the sialorrhea that is associated with ketamine administration in the company of maintained laryngeal reflexes can lead to laryngeal spasm when the throat is subjected to mechanical stimulus. When low-dose ketamine has been used in pediatric emergency settings, the incidence of laryngeal and bronchial spasm has been very low.13 

The new study by Eikermann et al .5raises several questions. One is whether or not the respiratory effects of ketamine are dose-dependent. A dose of approximately 1 mg/kg is perhaps the safest one in humans, but is it adequate for induction and maintenance of anesthesia under normal conditions? It currently is unusual to use ketamine as the only anesthetic outside of critical care conditions, but “low” doses (0.2–0.5 mg/kg) are used increasingly to complement other anesthetics in sedation and analgesia, including the management of chronic pain. Thus, a second question refers to the respiratory effect of these drug combinations and whether or not the patient is safer when ketamine is added. We believe so, but we need studies to confirm that combinations of ketamine and other drugs are safer than single-drug applications. Another question arises in relation to the available pharmaceutical preparations of ketamine. In most studies, including the one of Eikermann et al .5in this issue, the racemic form has been used, but we still lack information about the respiratory effects of differing enantiomeric proportions of S -ketamine and R -ketamine.

In summary, ketamine certainly will never become a first-line anesthetic, but it will keep its place as an excellent complementary drug and will become the subject of more research because of its wide margin of safety in relation to vital functions. A stronger role for ketamine in analgesia and procedural sedation for many diagnostic and therapeutic procedures seems appropriate, in adults as well as in children. The findings of Eikermann et al .,5that ketamine can be used in spontaneous ventilation and that the airway remains unobstructed, confirm that this anesthetic merits our confidence in its safety profile. Under these circumstances, ketamine has become a reasonable candidate for extended use,14and as we see it increasingly used by nonanesthesiologists for nonsurgical procedures outside the operating room, it is just possible that we may become embroiled in a new debate about how to use this drug appropriately.

Domino EF: Taming the ketamine tiger: 1965. ANESTHESIOLOGY 2010; 113:678–84
Domino EF, Chodoff P, Corssen G: Pharmacologic effects of CI-581, a new dissociative anesthetic in man. Clin Pharmacol Ther 1965; 6:279–91
Brown EN, Lydic R, Schiff ND: General anesthesia, sleep, and coma. N Engl J Med 2010; 363:2638–50
Corssen G, Domino EF: Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 1966; 45:29–40
Eikermann M, Grosse-Sundrup M, Zaremba S, Henry ME, Bittner EA, Hofmann U, Chamberlin NL: Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction. ANESTHESIOLOGY 2012; 116:35–46
Kobayashi I, Perry A, Rhymer J, Wuyam B, Hughes P, Murphy K, Innes JA, McIvor J, Cheesman AD, Guz A: Inspiratory coactivation of the genioglossus enlarges retroglossal space in laryngectomized humans. J Appl Physiol 1996; 80:1595–604
Oliven A, O'Hearn DJ, Boudewyns A, Odeh M, De Backer W, van de Heyning P, Smith PL, Eisele DW, Allan L, Schneider H, Testerman R, Schwartz AR: Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea. J Appl Physiol 2003; 95:2023–9
Nishino T, Yonezawa T, Honda Y: Different laryngeal responses during respiratory arrest produced by hypoxia withdrawal, thiopentone, ketamine, and lidocaine in cats. ANESTHESIOLOGY 1982; 56:280–5
Nishino T, Shirahata M, Yonezawa T, Honda Y: Comparison of changes in the hypoglossal and the phrenic nerve activity in response to increasing depth of anesthesia in cats. ANESTHESIOLOGY 1984; 60:19–24
Drummond GB: Comparison of sedation with midazolam and ketamine: Effects on airway muscle activity. Br J Anaesth 1996; 76:663–7
Saponjic J, Radulovacki M, Carley DW: Modulation of respiratory pattern and upper airway muscle activity by the pedunculopontine tegmentum: Role of NMDA receptors. Sleep Breath 2006; 10:195–202
Carson IW, Moore J, Balmer JP, Dundee JW, McNabb TG: Laryngeal competence with ketamine and other drugs. ANESTHESIOLOGY 1973; 38:128–33
Green SM, Roback MG, Krauss B, Emergency Department Ketamine Meta-Analysis Study Group: Laryngospasm during emergency department ketamine sedation: A case-control study. Pediatr Emerg Care 2010; 26:798–802
Green SM, Roback MG, Kennedy RM, Krauss B: Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med 2011; 57:449–61