Philipp Fassbender

Unwarranted Administration of Acetylcholinesterase Inhibitors Can Impair Genioglossus and Diaphragm Muscle Function

Background:It is standard practice to administer a cholinesterase inhibitor (e.g., neostigmine) at the end of a surgical case to reverse suspected effects of neuromuscular blocking agents regardless of whether such residual effects are present. The authors hypothesized that cholinesterase inhibition when given the in absence of neuromuscular blockade (NB) would decrease upper airway dilatory muscle activity and consequently upper airway volume. Methods:The authors measured genioglossus and diaphragm electromyograms during spontaneous ventilation in anesthetized, tracheostomized rats before and after administration of neostigmine (0.03, 0.06, or 0.12 mg/kg), after recovery of the train-of-four ratio (quadriceps femoris muscle) to unity after NB (n = 18). For comparison, the authors made the same measurements in rats that had no previous NB (n = 27). In intact anesthetized rats, the authors measured upper airway volume and end-expiratory lung volume by magnetic resonance imaging before and after 0.12 mg/kg neostigmine (n = 9). Results:Neostigmine treatment in rats that had fully recovered from NB based on the train-of-four ratio caused dose-dependent decreases in genioglossus electromyogram (to 70.3 ± 7.6, 49.2 ± 3.2, and 39.7 ± 2.3% of control, respectively), decreases in diaphragm electromyogram (to 103.1 ± 6.5, 83.1 ± 4.7, and 68.7 ± 7.3% of control), and decreases in minute ventilation to a nadir value of 79.6 ± 6% of preneostigmine baseline. Genioglossus electromyogram effects were the same when neostigmine was given with no previous NB. Neostigmine caused a decrease in upper airway volume to 83 ± 3% of control, whereas end-expiratory lung volume remained constant. Conclusions:The cholinesterase inhibitor neostigmine markedly impairs upper airway dilator volume, genioglossus muscle function, diaphragmatic function, and breathing when given after recovery from vecuronium-induced neuromuscular block.

Genioglossus premotoneurons and the negative pressure reflex in rats

Reflex increases in genioglossus (GG) muscle activity in response to negative pharyngeal pressure are important for maintenance of upper airway patency in humans. However, little is known of the central circuitry that mediates this negative pressure reflex (NPR). We used two approaches to determine which GG premotoneurons relay negative pressure‐related information to the hypoglossal motor nucleus. First, to identify GG premotoneurons, we injected pseudorabies virus (PRV152) into the GG muscle. We found that medullary GG premotoneurons were concentrated mainly in the reticular formation adjacent to the hypoglossal motor nucleus. Second, in order to determine whether these perihypoglossal neurons were involved in the NPR, we quantified GG EMG responses to negative pressure applied to the isolated upper airway in anaesthetized rats before and after microinjection of muscimol (9 nl; 0.25 mm), a GABA‐A receptor agonist, into the perihypoglossal premotor field. Pressures as low as −4 cmH2O increased inspiratory phase‐related GG activity. The NPR was abolished following bilateral injections of muscimol into the perihypoglossal premotor field at and up to 500 μm rostral to the obex. Muscimol in this location also increased the amplitude of basal, unstimulated phasic GG activity. By contrast, inhibition of neurons caudal to the obex decreased phasic GG activity but had no impact on the NPR. These results suggest that perihypoglossal GG premotoneurons near the obex mediate the NPR and those caudal to the obex are important mediators of respiratory‐related GG activity but are not involved in the NPR.

Differential Effects of Isoflurane and Propofol on Upper Airway Dilator Muscle Activity and Breathing

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.

Pentobarbital dose-dependently increases respiratory genioglossus muscle activity while impairing diaphragmatic function in anesthetized rats

Background:Anesthetics depress both ventilatory and upper airway dilator muscle activity and thus put the upper airway at risk for collapse. However, these effects are agent-dependent and may involve upper airway and diaphragm muscles to varying degrees. The authors assessed the effects of pentobarbital on upper airway dilator and respiratory pump muscle function in rats and compared these results with the effects of normal sleep. Methods:Tracheostomized rats were given increasing doses of pentobarbital to produce deep sedation then light and deep anesthesia, and negative pressure airway stimuli were applied (n = 11). To compare the effects of pentobarbital with those of natural sleep, the authors chronically instrumented rats (n = 10) with genioglossus and neck electromyogram and electroencephalogram electrodes and compared genioglossus activity during wakefulness, sleep (rapid eye movement and non–rapid eye movement), and pentobarbital anesthesia. Results:Pentobarbital caused a dose-dependent decrease in ventilation and in phasic diaphragmatic electromyogram by 11 ± 0.1%, but it increased phasic genioglossus electromyogram by 23 ± 0.2%. Natural non–rapid eye movement sleep and pentobarbital anesthesia (10 mg/kg intraperitoneally) decreased respiratory genioglossus electromyogram by 61 ± 29% and 45 ± 35%, respectively, and natural rapid eye movement sleep caused the greatest decrease in phasic genioglossus electromyogram (95 ± 0.3%). Conclusions:Pentobarbital in rats impairs respiratory genioglossus activity compared to the awake state, but the decrease is no greater than seen during natural sleep. During anesthesia, in the absence of pharyngeal airflow, phasic genioglossus activity is increased in a dose-dependent fashion.

Clinical Predictors of Duration of Action of Cisatracurium and Rocuronium Administered Long-Term

BACKGROUND The duration of action of neuromuscular blocking drugs (NBDs) varies between individuals and even within individuals in different settings. OBJECTIVES To define predictors of variance in duration of action of rocuronium and cisatracurium administered long-term. METHODS A prospective, double-blind, multicenter trial that included 113 patients scheduled for major abdominal surgery and postoperative admission to the intensive care unit. Patients received repetitive (median, 7) equipotent doses of rocuronium or cisatracurium to maintain deep relaxation (twitch height of the adductor pollicis muscle <25% of baseline). Effects of weight, age, sex, American Society of Anesthesiologists risk score, lowest core temperature, duration of NBD administration, and tobacco smoking history on duration of action of cisatracurium and rocuronium were determined via multiple regression analysis. RESULTS Only duration of NBD administration was predictive of the duration of action of rocuronium. The predicted increase in time to recovery of the train-of-4 ratio to 0.9 (duration TOF 0.9) per hour of continuous NBD treatment was 12.4 minutes. In contrast, only lowest core body temperature was predictive of cisatracuriums duration of action, and the predicted increase in duration TOF 0.9 per degree Celsius decrease was 9.8 min. CONCLUSION Duration of NBD treatment is strongly predictive of the duration of action of rocuronium, and body temperature is predictive of the duration of action of cisatracurium. These data may help decrease the incidence of drug-induced muscle weakness in recovery rooms and surgical intensive care units, particularly if neuromuscular transmission monitoring is not available.