Reversal of Nondepolarizing Neuromuscular Blockade
The cholinesterase inhibitors effectively antagonize the neuromuscular blockade caused by nondepolarizing drugs. Their general pharmacology is discussed in Chapter 7. Neostigmine and pyridostigmine antagonize nondepolarizing neuromuscular blockade by increasing the availability of acetylcholine at the motor end plate, mainly by inhibition of acetylcholinesterase. To a lesser extent, these cholinesterase inhibitors also increase the release of this transmitter from the motor nerve terminal. In contrast, edrophonium antagonizes neuromuscular blockade purely by inhibiting acetylcholinesterase activity. Edrophonium has a more rapid onset of action but may be less effective than neostigmine in reversing the effects of nondepolarizing blockers in the presence of profound neuromuscular blockade. These differences are important in determining recovery from residual block, the neuromuscular blockade remaining after completion of surgery and movement of the patient to the recovery room. Unsuspected residual block may result in hypoventilation, leading to hypoxia and even apnea, especially if patients have received central depressant medications in the early recovery period.
Sugammadex is a novel reversal agent recently approved for rapid reversal of the steroid neuromuscular blocking agents rocuronium and vecuronium. Although it has been in clinical use in Europe since 2008, its approval in the USA was delayed over concerns that it may cause anaphylaxis and hypersensitivity reactions. Sugammadex is a modified γ-cyclodextrin (a large ring structure with 16 polar hydroxyl groups facing inward and 8 polar carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the circulation, where it is quickly bound by free sugammadex.
Currently, three dose ranges are recommended for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and 16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium. In patients with normal renal function (defined as a creatinine clearance [CrCl] > 80 mL/min), the sugammadexrocuronium complex is typically excreted unchanged in the urine within 24 hours. In patients with renal insufficiency, complete urinary elimination may take much longer. The plasma half-life of sugammadex in patients with renal impairment increases significantly as CrCl is reduced. In mild to moderate renal insufficiency (CrCl between 30 and 80 mL/min), the half-life varies between 4 and 6 hours. This increases dramatically in patients with severe renal impairment (CrCl < 30 mL/min), in whom the half-life is extended to 19 hours. The ability to dialyze sugammadex is variable. Therefore, sugammadex is not recommended for use in patients with severe renal impairment.
Sugammadex is associated with a few significant adverse reactions. Most importantly, sugammadex may cause anaphylaxis, which occurred in 0.3% of patients who received the 16 mg/kg dose in the US Food and Drug Administration (FDA) studies. Hypersensitivity reactions, such as nausea, pruritus, and urticaria are more common than anaphylaxis, and also occur more frequently with higher doses of sugammadex. Other significant adverse reactions include marked bradycardia that may progress to cardiac arrest within minutes of administration and coagulopathy, with an approximately 25% elevation of activated partial thromboplastin time and prothrombin time/international normalized ratio values that may last up to 1 hour.