Efficacy of Sugammadex in Magnesium Pretreated Patients
Condition: Neuromuscular Block
Study type: Interventional
Phase: Phase 2

Summary: 
      Sugammadex is a new reversal agent for neuromuscular blockers (curare). It encapsulates the
      curare molecule and terminates immediately its action. The recommended dose is 2 mg/kg for a
      slight neuromuscular block and 4 mg/kg for a profound neuromuscular block. Magnesium sulphate
      is frequently used in perioperative medicine and it is known to reinforce the neuromuscular
      block induced for instance by rocuronium. The researchers want to investigate, whether higher
      doses of sugammadex must be given to antagonize the neuromuscular block induced by rocuronium
      in patients who received magnesium sulphate.
    

Detailed description: 
      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.
    

Intervention name(s): Magnesium Sulfate; Placebo comparator
Intervention type(s): Drug; Drug
Intervention description(s): 1ml/kg of the study solution containing 60 mg/ml of magnesium sulphate are given intravenously over 15 minutes in the conscious patient. After anaesthesia induction and calibration of neuromuscular monitoring (TOF Watch SX - acceleromyography) 0,6 mg/kg of rocuronium is given intravenously. After recovery of the neuromuscular block to a posttetanic count of 2 (deep neuromuscular block) (PTC 2) or reappearance of 2 twitches of the Train of four (superficial neuromuscular block) 4 mg/kg (deep neuromuscular block) or 2 mg/kg (superficial neuromuscular block) of Sugammadex are given intravenously.; 1ml/kg of the study solution containing physiologic saline are given intravenously over 15 minutes in the conscious patient. After anaesthesia induction and calibration of neuromuscular monitoring (TOF Watch SX - acceleromyography) 0,6 mg/kg of rocuronium is given intravenously. After recovery of the neuromuscular block to a posttetanic count of 2 (deep neuromuscular block) (PTC 2) or reappearance of 2 twitches of the Train of four (superficial neuromuscular block) 4 mg/kg (deep neuromuscular block) or 2 mg/kg (superficial neuromuscular block) of Sugammadex are given intravenously.
Intervention MeSH terms: Magnesium Sulfate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: sugammadex; rocuronium; magnesiumsulphate; neuromuscular monitoring