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Reversing Neuromuscular Blockade: Not Just the Diaphragm, but Carotid Body Function Too.

Neuromuscular blocking drugs have—for years—enabled anesthesiologists beneficially to relax skeletal muscles to improve anesthetic management, increase safety and quality of tracheal intubation, and to provide favorable intraoperative conditions for complex surgical procedures. While achieving these goals, a growing body of evidence has uncovered a price to pay in potential side effects, most frequently associated with the respiratory system having an increased risk of adverse pulmonary outcomes or, more rarely, “accidental intraoperative awareness,” which occurs almost exclusively in cases where neuromuscular blockade has been used. In the late 1990s, it was shown that subparalyzing concentrations of neuromuscular blocking drugs markedly impaired the acute ventilatory response to hypoxia in volunteers. Later animal studies located this effect to the carotid body, where these drugs blocked acetylcholine-dependent oxygen signaling pathways. In this issue of Anesthesiology, Broens et al. show that partial rocuronium block in volunteers depresses the acute ventilatory response to hypoxia—and also to hypercapnia. This confirms and extends earlier work, and also explores the effect of neuromuscular block reversal with neostigmine or sugammadex. A key finding is that even when the adductor pollicis train-of-four ratio had recovered to 1.0, the acute hypoxic response remained significantly depressed in several subjects. In this Editorial View, we will discuss the clinical implications of these results, and touch upon some relevant physiology. Importantly, resting minute ventilation in the study of Broens et al., and in the earlier works, was unaffected by partial paralysis, reflecting a maintained central respiratory drive. This drive originates from the background phasic activity of brainstem respiratory circuits. On the other hand, abrupt changes in arterial oxygen or carbon dioxide tensions trigger ventilatory responses via the carotid body chemoreflex which, in contrast to the phasic activity, reflects the system’s “responsiveness.” Thus, normal resting minute ventilation (phasic activity) does not necessarily mean that the patient will respond with hyperventilation to hypoxemia (responsiveness). Perioperative hypoxemia can arise for several reasons, and a weak reflex response can lead to adverse outcomes. Broens et al. found that reversal to a train-of-four ratio of 1.0 was still associated with depressed acute hypoxic response in some subjects. The human carotid body express nicotinic subunits α3, α7, and β2 of the pentameric neuronal subtype acetylcholine receptor, whereas muscle type receptors are pentamers of α1, β1, γ, δ, or ε subunits typically expressed in striated muscles. Importantly, neuromuscular blocking drugs have distinct affinity for both classes of acetylcholine receptors in clinically relevant dose ranges. In the neuromuscular junction, up to 75% of muscle type receptors must be occupied before there is detectable reduction in twitch tension; in contrast, neuronal cholinergic signaling is blocked in a dose-dependent manner. This could explain why hypoxic ventilatory control remains impaired even when neuromuscular function has recovered. Moreover, Broens et al. studied rocuronium as the sole drug administered. In clinical practice, there may be synergism with residual concentrations of