Efficacy of Sugammadex in Magnesium Pretreated Patients

Neuromuscular blocking agents (NMBAs) are frequently used in anaesthesia and intensive care medicine for tracheal intubation, artificial ventilation, and continued muscle relaxation during surgical interventions. Postoperative residual curarisation is associated with an increased risk of postoperative complications and morbidity. Consequently, adequate reversal of neuromuscular block after surgery is of great importance.

Cholinesterase inhibitors have been widely used as reversal agents. They increase the amount of acetycholine at the neuromuscular junction, which then competes with the NMBA to restore muscle function. Cholinesterase inhibitors have, however, a number of limitations. They antagonise the neuromuscular block slowly and are only effective when partial spontaneous recovery has already occurred. These agents are also associated with a relatively high incidence of cholinergic adverse reactions, including bradycardia, arrhythmia, salivation, and bronchoconstriction.

Sugammadex, a modified gamma cyclodextrin, is a selective binding agent specifically designed to encapsulate steroidal NMBAs such as rocuronium. It causes a rapid and complete reversal of neuromuscular blockade by preventing directly rocuronium to react on the neuromuscular receptor.

Dose-finding studies have suggested that sugammadex 2 mg kg-1 was needed for the reversal of a moderate neuromuscular block (reappearance of T2), and that doses ≥4 mg kg-1 were needed for the reversal of a profound block (1 to 2 post-tetanic counts). The median time for the recovery of a moderate neuromuscular block to a T4/T1 ratio of 0.9 (which is considered clinically safe) is around two minutes, and of a profound neuromuscular block is about three minutes.

Magnesium is sometimes used in perioperative medicine, for instance, to prevent seizures in parturients with pre-eclampsia. Magnesium has an impact on neuromuscular transmission. It reduces the amount of acetylcholine that is released at the motor nerve terminal, by decreasing the calcium conductance of presynaptic voltage-dependent calcium channels. After pre-treatment with a clinically relevant dose of magnesium sulphate (MgSO4), an increased speed of onset and a prolongation of the recovery period of the neuromuscular blockade have been observed with standard intubation doses of atracurium, vecuronium, and rocuronium. With rocuronium, for instance, the investigators recorded a shortening of the speed of onset of the neuromuscular block by about 35% but at the expense of a prolongation of the recovery period by about 25%. It has been shown that the interaction between magnesium and rocuronium may become relevant in specific clinical situations.

The clinically relevant interaction between MgSO4 and rocuronium begs the question as to whether in a patient who has received MgSO4, the efficacy of sugammadex to reverse a rocuronium-induced block may be affected. Indeed, animal studies have indicated that significantly higher doses of sugammadex might be needed to reverse a rocuronium-induced neuromuscular block after magnesium pretreatment.

The aim of this study is to test the hypothesis that the established doses of sugammadex for the fast and safe reversal of a moderate and a profound rocuronium-induced neuromuscular block are inadequate in patients who have received MgSO4. The investigators hypothesize that in subjects who received magnesium pretreatment, the time to reverse a moderate and a deep neuromuscular block (induced by a single intubation dose of rocuronium) with standard doses of sugammadex (2 and 4 mg kg-1, respectively) is prolonged by ≥ 50% and that the dose response curves will be displaced to the right (i.e. higher doses of sugammedex will be necessary to achieve the same speed of action as in patients who are not exposed to magnesium.