Reversal of Moderate (With the Use of Neostigmine 60 mcg/kg) or Superficial (With the Use of Neostigmine 30 mcg/kg) Neuromuscular Blockade Induced by Cisatracurium. A Prospective, Randomized, Controlled and Doubled Blinded Clinical Trial

INTRODUCTION One of the most frequent events after performing general anesthesia is the incomplete recovery from NMB. 1 Unfortunately, in addition to the unpleasant and unwanted sensation, post-operative residual muscle weakness can generate potentially more serious problems such as difficulty swallowing, airway obstruction, the occurrence of hypoxemia and pulmonary aspiration. 2,3 Hence, the importance of ensuring a complete reversal of non-depolarizing neuromuscular blocking agents before extubation. Traditionally, the administration of acetylcholinesterase inhibiting agents (such as neostigmine) has been used to reverse the muscle paralysis induced by the use of non-depolarizing neuromuscular blocking agents, but there are limitations related to the antagonism of deep neuromuscular blockade 4,5 or the occurrence of paradoxical effect, when excessive doses of neostigmine are administered during superficial blocks, causing muscle weakness 6,7. In view of this scenario, the need for quantitative assessment of neuromuscular monitoring through the stimulation of peripheral nerves is widely recognized to evaluate NMB reversal.3 During deep NMB [Train-of-Four (TOF) = 0 ; Post-Tetanic Count (PTC)> 1], the administration of neostigmine is likely to be inefficient and its administration is not indicated. In these cases, it would be more prudent to wait for the spontaneous regression of the NMB to less intense levels, when the action of neostigmine becomes more effective and safer.1 Even so, when there is light neuromuscular block (TOF = 4; T4 / T1> 0.4), the use of lower doses of neostigmine should be considered, as there is a risk of inducing paradoxical muscle weakness. 9 It is not well known whether there is a difference between the time required for complete reversion of moderate NMB after the administration of neostigmine in usual doses when compared to the reversion of superficial NMB with the use of a reduced dose of the same agent. The aim of the present study will be to compare, by means of a prospective, randomized, controlled and double-blind clinical trial, the times necessary for the reversion of TOF = 3 (moderate block) to T4 / T1 values> 0.9 (with neostigmine 60 mcg / kg) or for T4 / T1> 0.4 (superficial block) to reach values of T4 / T1> 0.9 (with neostigmine 30 mcg / kg). In addition, the times required for the reversion of TOF = 3 to T4 / T1> 0.4 and TOF = 3 to T4 / T1 = 1 will be evaluated, in addition to the probability of reversing the NMB in less than 10 minutes.

METHODS

After approval by the Research Ethics Committee of School of Medical and Health Sciences, Pontifical Catholic University of São Paulo (Sorocaba, São Paulo - Brazil), patients undergoing general anesthesia for nose and ear surgery at Hospital Santa Lucina will be enrolled to this prospective and randomized clinical trial. Patients aged between 18 and 65 years and physical status according to the American Society of Anesthesiologists I and II will be included. The exclusion criteria will be: (i) refusal to participate in the study; (ii) presence of kidney, liver or neuromuscular disease; (iii) contraindication to the use of any of the drugs used in the study or (iv) body mass index (BMI) ≥ 30. Patients will be randomly divided into four groups according to the moment of NMB reversal and the doses of neostigmine and atropine that will be administered:

• Group M (reversion with moderate NMB): administration of neostigmine 60 mcg/kg and atropine 30 mcg/kg when TOF (Train-of-Four) = 3 and saline when TOF (T4 / T1)> 0.4.
• Group S (reversion with superficial NMB): administration of 0.9% saline solution (SF) when TOF = 3 and neostigmine 30 mcg/kg and atropine 15 mcg/kg when TOF (T4 / T1)> 0.4.
• Group N (two-step reversal): neostigmine 30 mcg/kg and atropine 15 mcg/kg when TOF = 3 and neostigmine 30 mcg/kg and atropine 15 mcg/kg when TOF (T4 / T1)> 0.4 .
• Group C (control): administration of 0.9% saline solution (SF) when TOF = 3 and when TOF (T4 / T1)> 0.4.

For each patient, an opaque envelope will be prepared, sealed and numbered sequentially containing the group to which the patient will be allocated. A list of random numbers generated by computer (www.random.org), in blocks of 1: 1: 1: 1, will be used for this purpose. No collaborator in the operating room, surgeon or anesthesiologist involved in the control of anesthesia and data collection will be aware of the content of the solutions (neostigmine with atropine or saline). An anesthesiologist not involved in the study will be responsible for preparing the solutions: