Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction

Abstract

Background: Procedural sedation is frequently performed in spontaneously breathing patients, but hypnotics and opioids decrease respiratory drive and place the upper airway at risk for collapse.

Methods: In a randomized, controlled, cross-over, pharmaco-physiologic study in 12 rats, we conducted acute experiments to compare breathing and genioglossus electromyogram activity at equianesthetic concentrations of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that combines potent analgesic with hypnotic action effects, versus propofol. In 10 chronically instrumented rats resting in a plethysmograph, we measured these variables as well as electroencephalography during five conditions: quiet wakefulness, nonrapid-eye-movement sleep, rapid eye movement sleep, and low-dose (60 mg/kg intraperitoneally) and high-dose ketamine anesthesia (125 mg/kg intraperitoneally).

Results: Ketamine anesthesia was associated with markedly increased genioglossus activity (1.5 to fivefold higher values of genioglossus electromyogram) compared with sleep- and propofol-induced unconsciousness. Plethysmography revealed a respiratory stimulating effect: higher values of flow rate, respiratory rate, and duty-cycle (effective inspiratory time, 1.5-to-2-fold higher values). During wakefulness and normal sleep, the δ (f = 6.51, P = 0.04) electroencephalogram power spectrum was an independent predictor of genioglossus activity, indicating an association between electroencephalographic determinants of consciousness and genioglossus activity. Following ketamine administration, electroencephalogram power spectrum and genioglossus electroencephalogram was dissociated (P = 0.9 for the relationship between δ/θ power spectrum and genioglossus electromyogram).

Conclusions: Ketamine is a respiratory stimulant that abolishes the coupling between loss-of-consciousness and upper airway dilator muscle dysfunction in a wide dose-range. Ketamine compared with propofol might help stabilize airway patency during sedation and anesthesia.

Figure 1. Protocols

Protocol 1: Acute experiments. In a randomized, cross-over study, rats were instrumented during isoflurane anesthesia. Subsequently, median effective dose values were calculated individually (Dixon’s up-and-down method), and measurements of breathing, blood pressure, electrocardiogram, pharyngeal pressure, and genioglossus electromyogram were taken at three different effective doses of ketamine and propofol. Protocol 2: Experiments in chronically instrumented rats. After instrumentation with genioglossus muscle, neck muscle, and epidural electroencephalography electrodes, rats were allowed to recover for 7 days. Subsequently, measurements of breathing, electroencephalogram, and muscle activity were made in a plethysmography chamber during wakefulness, sleep, and ketamine anesthesia (two different doses). EMG = electromyogram, ED50 = median effective dose, GG = genioglossus, EEG = electroencephalogram, iv = intravenous, mg = milligram, kg = kilogram

Figure 2. Sample recordings from an acute experiment

A: Ketamine anesthesia. Note that genioglossus electromyogram, and respiratory flow increase with ketamine dose, while end-tidal carbon dioxide remains constant. B: Propofol anesthesia. Note that genioglossus electromyogram and respiratory flow decrease with propofol dose, while end-tidal carbon dioxide increases. ED50 = median effective dose, AU = arbitrary units, GG = genioglossus, ET CO2 = end tidal carbon dioxide, MTA = moving time average, EMG = electromyogram, resp. flow = respiratory flow, mV = millivolt, ml = milliliter, min = minute, mmHg = millimeters of mercury

Figure 3. Representative recordings from a chronically instrumented rat

Measurements during sleep (A+B) and ketamine anesthesia (C+D). Note that genioglossus electromyogram was higher during ketamine anesthesia compared with sleep. During ketamine anesthesia, strong respiratory activity was present during wakefulness and sleep. The electroencephalogram during nonrapid eye movement sleep and ketamine anesthesia appears similar (predominantly slow-wave sleep), but different from rapid eye movement sleep (predominantly theta waves). 5 s epoch. GG = genioglossus, EMG = electromyogram, EEG = electroencephalogram, NREM = nonrapid eye movement sleep, REM = rapid eye movement sleep, uV = microvolt, ml = milliliter, s = second

Figure 4. Chronically instrumented rats: Electroencephalography and electromyography measurements

A: Electroencaphalography Power Spectrum. Please note that the electroencephalogram during slow wave sleep and ketamine anesthesia look similar (high slow-wave frequency power), but different from wakefulness and rapid eye movement sleep. B: Neck muscle electromyogram: neck muscle electromyogram was significantly higher during low-dose, but not during high-dose ketamine anesthesia compared with (quiet) wakefulness and sleep. C: Genioglossus electromyogram: Genioglossus electromyogram was significantly higher during ketamine anesthesia compared with wakefulness and sleep. * p < 0.05 versus low-dose ketamine anesthesia (60 mg/kg) # p < 0.05 versus high-dose ketamine anesthesia (125 mg/kg) REM = rapid eye movement sleep, SWS = slow wave sleep, hi K = high-dose ketamine anesthesia, lo K = low-dose ketamine anesthesia, EMG = electromyogram, mg = milligram, kg = kilogram

Figure 5. Acute experiments: Breathing of tracheostomized rats during ketamine (circles) and propofol (squares) anesthesia

During ketamine anesthesia breathing, represented by respiratory rate (A), tidal volume (B), minute ventilation (C), and flow rate (D), was augmented compared with propofol. Based on augmented breathing during ketamine anesthesia, duty-cycle (E) is increased, resulting in lower end-tidal carbon dioxide (F) values compared with propofol. * p < 0.05 for dose-effect (within anesthetic agent). + p < 0.05 for an interaction effect (between anesthetic agents). # p < 0.05 versus propofol, same effective dose (post-hoc test). ED50 = median effective dose, min = minute, min⁻¹ = per minute, ml = milliliter, s = second, Vt = tidal volume, TI = inspiratory time, Ttot = total respiratory cycle time, mmHg = millimeters of mercury

Figure 6. Acute experiments: Phasic and tonic genioglossus activity during ketamine and propofol anesthesia. Genioglossus electromyogram was significantly higher during ketamine compared with propofol anesthesia. Phasic activity dose-dependently increased during ketamine and decreased during propofol anesthesia

A: Phasic genioglossus activity dose-dependently increased during ketamine anesthesia and decreased during propofol anesthesia. B: Tonic genioglossus activity increased during median effective dose of ketamine and decreased during high dose ketamine and propofol anesthesia. * p <0.05 for dose-effect (within anesthetic agent). + p <0.05 for an interaction effect (between anesthetic agents). # p <0.05 versus propofol, same effective dose (post-hoc test). ED50 = median effective dose

Figure 7. Chronically instrumented rats: Respiratory parameters following ketamine administration compared to those during spontaneous sleep and wake. Measurements were taken in a whole-body plethysmograph during wakefulness, sleep, and ketamine anesthesia. A: respiratory rate, B: tidal volumes, C: minute ventilation, D: Duty cycle, E: Flow rate

Ketamine stimulated breathing: respiratory rate (A), flow-rate (E), and duty-cycle (D) were significantly higher during ketamine anesthesia compared with wakefulness and sleep. Note that rats were chronically instrumented and breathing by the normal anatomical route. * p <0.05 versus low-dose ketamine anesthesia (60 mg/kg) # p <0.05 versus high-dose ketamine anesthesia (120 mg/kg) NREM = nonrapid eye movement sleep, REM = rapid eye movement sleep, bpm = breaths/min, ml = milliliter, TI = inspiratory time, Ttot = total respiratory cycle time, s = second, mg = milligram, kg = kilogram

Figure 8. Chronically instrumented rats: Relation between electroencephalogram power spectrum and genioglossus electromyogram in chronically instrumented rats. Five repetitive measurements from eight rats. Red symbols: Wakefulness, blue symbols: nonrapid eye movement sleep, green symbols: rapid eye movement sleep, turquois symbols: low-dose ketamine anesthesia (60 mg/kg), black symbols: high-dose ketamine anesthesia (125 mg/kg)

A+B: Not anesthetized: genioglossus electromyogram positively correlates with delta activity (A). There is a trend towards negative correlation with theta activity (B). C+D: During ketamine anesthesia: the relation between electroencephalogram and electromyogram is abolished, i.e., sleep and genioglossus dysfunction are uncoupled. EEG = electroencephalogram, EMG = electromyogram, AU = arbitrary units, REM = rapid eye movement sleep, mg = milligram, kg = kilogram