Interaction Between Intravenous Magnesium Sulphate and Neostigmine or Sugammadex for the Reversal of a Rocuronium-induced Neuromuscular Block - A Randomized, Double Blinded, Electrophysiological Study

Magnesium sulphate (MgSO4) is regularly used in perioperative medicine. For instance, pre-eclampsia and eclampsia have been successfully treated with intravenous magnesium. Also, MgSO4 has been used for the control of life threatening cardiac arrhythmias, bronchial asthma or as an anticonvulsant. Finally, magnesium has been found to alleviate postoperative pain and to exert morphine sparing effect.

Magnesium plays a role in nearly every physiological system. In the nervous system, magnesium has a depressant effect related to the inhibition of transmitter release from presynaptic sites by competing with calcium and due to the antagonism at NMDA receptors. The presynaptic inhibition of acetylcholine release at the neuromuscular junction by magnesium has been well described. In addition, an excess of magnesium ions diminishes the depolarizing action of acetylcholine at the end-plate, and depresses the excitability of the muscle fiber membrane. Magnesium per se causes significant neuromuscular blockade (NMB) in high concentrations (≥ 5 mmol L-1). In the presence of curare-like agents, however, very low concentrations of magnesium (≥1 mmol L-1) inhibit neuromuscular transmission since in this case much more acetylcholine is needed to produce a magnitude of depolarization of the end-plate compared with normal conditions. Consequently, magnesium enhances the effect of muscle relaxants during and after general anesthesia. The prolongation of the duration of NMB by magnesium may increase the incidence of a residual postoperative neuromuscular block, and consequently may compromise patient safety. In addition, magnesium, when administered immediately after spontaneous recovery of a NMB, may cause recurrence of the NMB ("recurarisation"). Under clinical conditions this may happen whenever magnesium is used in the immediate postoperative period, for instance, for postoperative pain alleviation or for treatment of postoperative cardiac arrhythmia.

It is not known, however, whether pharmacological reversal of a NMB prior to magnesium treatment prevents the recurrence of NMB. Recovery after neostigmine (an anticholinestherase agent) administration was approximately 30% less in patients pretreated with MgSO4 compared with those without MgSO4 pretreatment. Sugammadex, a γ-cyclodextrin compound, is a new reversal agent. It is a specific encapsulator of steroidal muscle relaxants such as rocuronium. We have demonstrated that magnesium pretreatment did not prolong the reversal of deep or moderate rocuronium-induced neuromuscular blockade when standard doses of sugammadex were used for reversal.

Sugammadex causes a rapid and complete reversal of the neuromuscular blockade by reducing the action of rocuronium on the prejunctional and postjunctional nicotinic acetylcholine receptors (nAChRs). Unlike neostigmine, sugammadex is efficacious in reversing moderate (2 twitches to train-of-four [TOF] stimulation, TOF-count two [TOFC-2]) and deep (post-tetanic count [PTC] of 1 or 2) rocuronium-induced NMB in doses of 2.0 mg kg-1 and 4.0 mg kg-1, respectively.

The suggested cause of return of NMB ("recurarisation") subsequent to magnesium administration is the absence of a functional reserve of the neuromuscular junction (safety margin, 70% of receptor capacity) despite a complete recovery of the TOF ratio and twitch amplitude (T1) (main variables of neuromuscular monitoring). It is important to know that the actually available neuromuscular monitoring methods are insensitive to measure the safety margin of the neuromuscular transmission, thus they cannot provide information about the likelihood of block recurrence. Theoretically, recurrence of a NMB due to clinical doses of magnesium happens only in cases where the safety margin is reduced or abolished by a NMB agent. Therefore, to prevent recurrent muscle weakness ideally all relaxant molecules should be eliminated from the neuromuscular synapse before magnesium is administered.