Unwarranted administration of acetylcholinesterase inhibitors can impair genioglossus and diaphragm muscle function

Abstract

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.

Fig. 1

Protocols. Protocol 1: Assessment of neostigmine effects on respiratory muscle function and breathing. We did not administer neuromuscular blocking drugs (NBDs) in this protocol. Protocol 2: Assessment of respiratory muscle function and breathing effects of neostigmine when administered after recovery of the train-of-four (TOF) ratio to unity from vecuronium-induced neuromuscular blockade. Protocol 3: Magnetic resonance imaging (MRI) of upper airway volume and end-expiratory lung volume before and after neostigmine. Active control = glycopyrrolate or atropine. AMD = antimuscarinergic drug; Dia = diaphragm; EMG = electromyogram; GG = genioglossus muscle; UAW = upper airway.

Fig. 2

Peak effects of neostigmine on genioglossus electromyogram (EMG) (squares) and the diaphragm EMG (circles). Solid lines, closed symbols = neostigmine given without previous vecuronium administration (protocol 1); dashed lines, open symbols = neostigmine given after recovery of the train-of-four ratio from neuromuscular blockade (protocol 2). Values are given in percent of control values observed before neostigmine injection. * P < 0.05, dose effect, same muscle, same protocol (vs. 0.03 mg/kg). # P < 0.05, dose effect significantly lower than diaphragm (same protocol). & P < 0.05 versus baseline (before neostigmine injection, paired t test).

Fig. 3

Typical response to administration of neostigmine. Genioglossus (GG) electromyogram (EMG; raw signal and moving time average [MTA]), diaphragm (Dia) EMG (rectified raw signal and MTA), respiratory (Resp) flow, and blood pressure (BP) (from top to bottom) before and after administration of 0.06 mg/kg neostigmine without previous administration of neuro-muscular blocking drug (protocol 1). Twenty seconds after neostigmine, phasic activity of the genioglossus and diaphragm were markedly decreased.

Fig. 4

Time course of recovery of the genioglossus (open circles) and diaphragm (closed circles) electromyogram (EMG) from 0.06 mg/kg neostigmine. No vecuronium had been given previously (protocol 1). Values of variables were averaged every minute until maximum recovery. Diaphragm and genioglossus EMG varied on a breath-by-breath basis (fig. 3). EMG recovery was significantly faster at the diaphragm compared with the genioglossus muscle. * P < 0.05 for between-groups effects (genioglossus vs. diaphragm).

Fig. 5

Peak effects of neostigmine on minute ventilation, respiratory rate, and tidal volume in rats. (A) Effect of neostigmine on minute ventilation after recovery from neuromuscular blockade. Neostigmine administered after recovery from vecuronium neuromuscular block impaired minute ventilation in tracheostomized rats. (B) Effect of neostigmine (no previous neuromuscular blockade). Rats developed rapid shallow breathing, but minute ventilation remained constant. * P < 0.05 versus baseline. + P < 0.05 for between-groups effects (with vs. without previous vecuronium injection).

Fig. 6

Effects of 0.12 mg/kg neostigmine on upper airway structure. (A) Cross-sectional areas (CSAs) of rat upper airway. The sagittal view shows the rat in the prone position. Measurements were made from the junction of the soft and hard palate (cranial margin) down to 9 mm below (area of the vocal cords). CSAs are significantly decreased after injection of neostigmine. (B) Upper airway volume at baseline, immediately after injection of neostigmine and 45 min after injection (recovery). Individual data (open symbols) and mean ± SEM (closed symbols with error bars). Upper airway volume was significantly decreased with neostigmine, and mean values recovered 45 min after drug injection.