Ketamine: a familiar drug we trust.

K ETAMINE, like many other drugs, was the fruit of investigative labors shared by anesthesiologists and pharmacologists, as recently described by Domino in 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. Now 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. 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 Domino recruited 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. contribute 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 ED50 and 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. Hypotonia 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.