Interaction Between Magnesium and Neostigmine or Sugammadex for the Reversal of a Rocuronium-induced Neuromuscular Block
Condition: Neuromuscular Blockade
Study type: Interventional
Phase: Phase 4

Summary: 
      Magnesium sulphate is regularly used in perioperative medicine. During and after general
      anesthesia, it enhances the effect of muscle relaxants because it reduces the liberation of
      acetylcholine at the neuromuscular junction. When administered immediately after spontaneous
      recovery of a neuromuscular block (NMB), magnesium may cause a recurrence of NMB and
      compromise patient safety.

      Rocuronium is a neuromuscular blocking agent which is frequently used to facilitate
      intubating and surgical conditions. At the end of the procedure, there are two ways to
      accelerate the reversal of a neuromuscular block induced by rocuronium: 1. Administration of
      neostigmine, an anticholinesterase agent and competitive antagonist; 2. Administration of
      sugammadex, a γ-cyclodextrin compound and specific encapsulator of rocuronium.

      The study is done in patients receiving rocuronium and either neostigmine or sugammadex for
      reversal of NMB. It is hypothesized that when sugammadex is used as an antagonist of a
      rocuronium-induced NMB, it prevents the reappearance of NMB when magnesium is injected,
      because sugammadex should inactivate all remaining rocuronium molecules and restore
      neuromuscular reserve of the neuromuscular junctions. Further more it is hypothesized that
      reversal with neostigmine will not prevent a magnesium-induced recurrence of NMB to the same
      extent. The primary objective of the study is to show that after reversal with sugammadex
      there is no or only very little re-occurrence of neuromuscular block after a magnesium
      perfusion. Furthermore we want to show that after reversal with neostigmine there is a
      re-occurrence of neuromuscular block.
    

Detailed description: 
      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.

      Pharmacological reversal of NMB reduces neuromuscular receptor occupancy and thereby
      increases the safety margin. Neostigmine augments the amount of acetylcholine at the
      neuromuscular junction, which competitively antagonizes the NMB and liberates at least
      partially the synaptic receptor reserves. However, neostigmine is not reliable to completely
      re-establish neuromuscular function. When sugammadex is administered, the free rocuronium
      plasma concentration rapidly declines near to zero (like a washout) and consequently the
      safety margin isincreased. In this context, one can speculate that sugammadex is an ideal
      antagonist when magnesium treatment is associated with the use of rocuronium.

      However, it is still unknown whether the administration of magnesium sulphate immediately
      after pharmacological reversal of the TOF ratio to a normalized 0.9 value (i.e. adequate
      reversal) re-induces a clinically relevant NMB. If magnesium is used in the immediate
      postoperative period, we need to know whether, and how, postoperative muscle paralysis as a
      consequence of the magnesium treatment can be prevented.

      The hypothesis of this study is that when sugammadex is used as an antagonist of a
      rocuronium- induced NMB, the neuromuscular junction will be liberated from almost all
      rocuronium molecules and no recurrent NMB will occur. Furthermore it is hypothesized that
      reversal with neostigmine will not prevent to the same extent magnesium-induced recurrence of
      NMB. In addition, the magnitude and time course of the magnesium induced neuromuscular block
      will be measured.
    

Intervention name(s): Magnesium Sulfate
Intervention type(s): Drug
Intervention description(s): After reversal the obention of a TOF ratio of 0.9 is avaited. 10 minutes later patients will receive a perfusion of magnesium 60 mg kg-1 over 5 minutes.
Intervention MeSH terms: Magnesium Sulfate
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 2 arms, randomized, double blind trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: rocuronium, magnesium sulphate, neostigmine, sugammadex