Differential effects of isoflurane and propofol on upper airway dilator muscle activity and breathing

Abstract

Background: Anesthesia impairs upper airway integrity, but recent data suggest that low doses of some anesthetics increase upper airway dilator muscle activity, an apparent paradox. The authors sought to understand which anesthetics increase or decrease upper airway dilator muscle activity and to study the mechanisms mediating the effect.

Methods: The authors recorded genioglossus electromyogram, breathing, arterial blood pressure, and expiratory carbon dioxide in 58 spontaneously breathing rats at an estimated ED50 (median effective dose) of isoflurane or propofol. The authors further evaluated the dose-response relations of isoflurane under different study conditions: (1) normalization of mean arterial pressure, or end-expiratory carbon dioxide; (2) bilateral lesion of the Kölliker-Fuse nucleus; and (3) vagotomy. To evaluate whether the markedly lower inspiratory genioglossus activity during propofol could be recovered by increasing flow rate, a measure of respiratory drive, the authors performed an additional set of experiments during hypoxia or hypercapnia.

Results: In vagally intact rats, tonic and phasic genioglossus activity were markedly higher with isoflurane compared with propofol. Both anesthetics abolished the genioglossus negative pressure reflex. Inspiratory flow rate and anesthetic agent predicted independently phasic genioglossus activity. Isoflurane dose-dependently decreased tonic and increased phasic genioglossus activity, and increased flow rate, and its increasing effects were abolished after vagotomy. Impairment of phasic genioglossus activity during propofol anesthesia was reversed during evoked increase in respiratory drive.

Conclusion: Isoflurane compared with propofol anesthesia yields higher tonic and phasic genioglossus muscle activity. The level of respiratory depression rather than the level of effective anesthesia correlates closely with the airway dilator muscle function during anesthesia.

Figures

Fig. 1

Protocols. Protocol 1: After surgery, we determined the ED50 (median effective dose) of propofol or isoflurane to compare the effects of equianesthetic doses of these anesthetics on genioglossus activity and breathing. In isoflurane-anesthetized animals, we subsequently measured these variables at two additional dose levels, i.e., 1.49 ± 0.01 (ED50) (n = 12) and either 2% or 2.25% (n = 6 each). Protocol 2: We evaluated the effects of different interventions on the dose–response relation of isoflurane at the genioglossus muscle and breathing. In a subset of 6 chronically instrumented animals, we compared the effect of light isoflurane anesthesia between wakefulness and light anesthesia (1% isoflurane). Protocol 3: We evaluated during propofol anesthesia the effects on genioglossus muscle electromyogram of conditions that increased respiratory drive (hypoxia and hypercapnia) to flow rate values that were similar to those observed during isoflurane anesthesia. CO2 = carbon dioxide; KF = Kölliker-Fuse nucleus; NP = negative pharyngeal pressure application.

Fig. 2

Genioglossus activity and flow rate during isoflurane (ED50 [median effective dose]) and propofol (ED50). Values are given in microvolts. * P < 0.05 versus isoflurane. A–C: Data from protocol 1 (n = 18). D: Pooled data from protocols 1 and 2 (n = 46). (A) Phasic genioglossus activity measured at time of assessment of genioglossus activity. Genioglossus activity was significantly lower during propofol anesthesia compared with isoflurane, and carbon dioxide levels were higher (82 ± 3 vs. 41 ± 1 vs. mmHg; P < 0.05). (B) Tonic genioglossus activity. Tonic genioglossus activity was significantly lower during propofol anesthesia compared with isoflurane. (C) Flow rate. Flow rate was significantly lower (P < 0.05) during propofol anesthesia compared with isoflurane. MTA = moving time average. (D) Phasic genioglossus activity at ED50 (given as rate of MTA rise) as a function of flow rate. Pooled data from protocols 1–3 (n = 53). Flow rate correlated significantly with phasic genioglossus activity. r = 0.47, P < 0.05. Open circles = isoflurane; closed circles = propofol.

Fig. 3

Effects of isoflurane on genioglossus activity and respiratory function. Data are mean ± SEM. (A) Phasic genioglossus activity at different isoflurane concentrations. Repetitive measurements at 1.0% (n = 12), 1.49 ± 0.01 (ED50) (n = 12), and 2% (n = 6) or 2.25% (n = 6) isoflurane. Phasic genioglossus activity increased dose dependently with isoflurane dose but was significantly lower at 2.25% versus 1.49 ± 0.01 (ED50) (paired t test). * P < 0.05 for increase of genioglossus activity with isoflurane dose (linear mixed model). + P < 0.05 versus 1.49 ± 0.01 (ED50) isoflurane (paired t test). (B) Flow rate. Flow rate (tidal volume/inspiration time) increased significantly with isoflurane dose. * P < 0.05 for dose effect (linear mixed model). # P < 0.05 versus 1.49 ± 0.01 (ED50) isoflurane (paired t test). (C) Increase in flow rate from 1–2% isoflurane versus increase in genioglossus activity from 1–2% isoflurane. Isoflurane evoked increase in genioglossus activity correlated significantly with evoked increase in flow rate (r = 0.6, P < 0.05; n = 35 rats). MTA = moving time average.

Fig. 4

Influence of vagal nerve section on genioglossus activity and breathing. Open circles = vagal nerves intact; diamonds = vagotomized rats. Data are mean ± SEM. * P < 0.05 for dose effects of isoflurane (within groups). # P < 0.05 versus controls (between-subjects effects). (A) Phasic genioglossus activity. At 1% isoflurane, phasic genioglossus activity was significantly higher in vagotomized rats compared with controls. Isoflurane increased genioglossus activity dose dependently in controls, whereas it decreased it in vagotomized rats. (B) Flow rate. At 1% isoflurane, flow rate was significantly higher in vagotomized rat compared with controls.

Fig. 5

Effects of hypoxemia and hypercapnia on phasic genioglossus activity, and flow rate during propofol anesthesia (ED50 [median effective dose]). Arterial partial pressures of carbon dioxide and oxygen concentration were measured at time of assessment (mean and SEM). * P < 0.05 versus condition 1 (paired t test). CO2 = carbon dioxide; et = end-tidal; O2 = oxygen. (A) Phasic genioglossus activity. Genioglossus activity increased significantly during evoked hypoxemia and hypercapnia. (B) Flow rate (tidal volume/inspiratory time). Flow rate increased significantly during evoked hypoxemia and hypercapnia. (C) Minute ventilation. Minute ventilation decreased significantly during propofol anesthesia and increased subsequently during evoked hypoxemia and hypercapnia. * P < 0.05 versus before evoked hypoxemia/ hypercapnia.

Fig. 6

(A) Genioglossus negative pressure reflex. The increase in phasic genioglossus activity in response to negative pharyngeal pressure application was inhibited with increasing isoflurane concentrations. * P < 0.05 for decreasing genioglossus negative pressure effects with increasing isoflurane dose, and for lower values at 2% isoflurane compared with 1% isoflurane. (B and C) Tonic activity of genioglossus muscle. Data are percent of values measured at 1% isoflurane. (B) Nonanesthetized state versus 1% isoflurane (n = 6). Chronically instrumented rats. Tonic activity of genioglossus muscle was significantly higher under room air compared with anesthesia. * P < 0.05 versus non-anesthetized rats. (C) Dose–response effect of isoflurane. Isoflurane dose-dependently decreased tonic genioglossus activity. Data from 12 rats. * P < 0.05 for decreasing tonic genioglossus activity with increasing isoflurane dose, and for lower values at 2% isoflurane compared with 1% isoflurane.