Comparing Reversal With Neostigmine and Sugammadex in Paediatric
Condition: Neuromuscular Blockade
Study type: Interventional

Summary: 
      A reversal agent is commonly given to improve neuromuscular function after intra-operative
      administration of non-depolarizing neuromuscular blocking agents. The administration of
      conventional reversal agent neostigmine is associated with many undesirable side effects. For
      almost a decade, a new novel drug sugammadex has been used to specifically antagonize the
      effect of aminosteroidal neuromuscular blocking agents.

      A total of 80 paediatric patients planned for general anaesthesia were divided into two
      groups and were given either neostigmine+atropine, or sugammadex for reversal once the
      operation had completed.
    

Detailed description: 
      RESEARCH HYPOTHESIS

        1. Sugammadex has a shorter recovery time (from TOF count of 2 or 3 to TOF ratio of more
           than 0.9) as compared to neostigmine.

        2. Sugammadex has a more stable haemodynamic profile as compared to neostigmine when used
           to reverse rocuronium induced neuromuscular blockade in paediatric patients.

        3. Sugammadex causes less complications or side effects when used in paediatric patients as
           a reversal for rocuronium induced neuromuscular blockade when compared to neostigmine.

      This study was a prospective, double blinded, randomized control study involving 80 selected
      paediatric patients undergoing various surgeries under general anaesthesia in the operation
      theatre of Hospital University Sains Malaysia (USM), Kubang Kerian.

      Sample size The sample size for this study was calculated using Power and Sample Size
      Calculation Programme Version 3.0.10.software based on different each respective objectives.

        1. To compare the recovery time from Train of four (TOF) count of 2 or 3 to TOF ratio of
           more than 0.9 between neostigmine and sugammadex in reversal of rocuronium induced
           neuromuscular blockade in paediatric patients.

           • For objective 1, 33 participants in each respective groups are needed to detect the
           difference of 8 minutes (480 seconds) in time taken to achieve TOF ratio of 0.9
           post-administration of reversal agent (SD was 590, according to Olzem Sacan et al) with
           90% power, alpha 0.05. 20% is added for drop out participant. Therefore sample size, n =
           33 + (0.2 x 33) = 40 patients.

        2. To compare the haemodynamic changes between neostigmine and sugammadex in reversal of
           rocuronium induced neuromuscular blockade in paediatric patients.

             -  For objective 2 (referring to blood pressure), 22 participants in each respective
                groups are needed to detect the difference of 10 mmHg in mean arterial blood
                pressure 5 minutes post-administration of reversal agent (SD was 10, according to
                Olzem Sacan et al) with 90% power, alpha 0.05. 20% is added for drop out
                participant. Therefore sample size, n = 22 + (0.2 x 22) = 26 patients.

             -  For objective 2 (referring to heart rate), 22 participants in each respective
                groups are needed to detect the difference of 8 beats per minute in heart rate, 5
                minutes post-administration of reversal agent (SD was 8, according to Olzem Sacan
                et al) with 90% power, alpha 0.05. 20% is added for drop out participant. Therefore
                sample size, n = 22 + (0.2 x 22) = 26 patients.

      Therefore the total patients in each group will be 40 patients per group. Total sample size
      is 80 patients.

      After gaining approval from USM Research Ethics Committee, the study was conducted in the
      Operation Theatre Hospital University Sains Malaysia (HUSM).

      Parents of patients who fulfilled the inclusion criteria for this study were counselled, and
      those who agreed to participate in the study were given full explanation about the study and
      written consent was taken.

      Randomization Subjects were divided into two groups using allocation sequence generated from
      online randomisation software (http://www.randomization.com). These respective allocations
      were concealed in sealed envelopes, which were not opened until it was time to administer the
      respective reversal agents in the Operation Theatre after completion of surgery. Patients
      were randomised to receive either 'Drug A' or 'Drug B' to reverse rocuronium induced
      neuromuscular blockade.

      The randomization generated by the computer was only known to the anaesthetic assistant
      nurse, who is not involved in recruiting patients or carrying out the study.

      Blinding This is a double blinded study. There were 2 important measures taken to ensure
      this. For this purpose, a specific anaesthetic assistant nurse is allocated before the study
      was carried out. This nurse is not involved in recruiting the subjects or carrying out the
      study, and is not related to the researcher.

      Step 1 : Prior to sample collection, all subjects have already been randomized according to a
      sequence derived from online computer randomization. The anaesthetic assistant nurse prepares
      80 envelopes, each respectively numbered 1-80, and 80 cards that will fit into the envelope,
      40 labelled 'A' and 40 labelled 'B'. The cards were inserted into the envelopes and sealed
      according to the sequence that was derived from computer randomization. For example if
      subject 1 falls under group A, the card labelled 'A' is inserted into the envelope labelled
      1, and firmly sealed. This is continued until all 80 cards have been inserted into all 80
      numbered envelopes according to the determined sequence, all being firmly sealed. This
      process is carried out without the presence of the researcher.

      Step 2 : On the day of surgery, prior to inducing the patient under general anaesthesia, the
      anaesthetic assistant nurse had prepares the reversal agents labelled 'Drug A' and 'Drug B'.
      To ensure desired double blinding, both reversal agents had to be diluted into similar
      volumes for equivalent dose for each respective drug for reversal of moderate block of
      Rocuronium induced neuromuscular blockade (TOF count 2 or 3)

        -  1 mg of Atropine (1ml) was mixed with 2.5mg of Neostigmine (1ml) and diluted into 10 mls
           with Normal Saline 0.9% in a 10ml standard syringe. This would be a solution of 0.1
           mg/ml Atropine with 0.25 mg/ml Neostigmine. A normal standard reversal dose for TOF
           count of 2 to 3 would be 0.05 mg/kg of Neostigmine with 0.02 mg/kg of Atropine.
           Therefore the volume would be 0.2mls per kg.

        -  100 mg Sugammadex (1ml) is diluted into 10mls in a standard 10mls syringe with Normal
           Saline 0.9%. This will provide a new solution of 10mg/ml. The required dose for reversal
           of reversal of Rocuronium induced neuromuscular blockade with a TOF count of 2 or 3
           would be 2mg/kg. This will also be equivalent to a volume of 0.2mls per kg.

      This process was also done without the presence of the researcher. All medications were
      discarded by the end of the day.

      Only the anaesthetic assistant nurse is aware which drug, either Neostigmine-Atropine
      combination or Sugammadex belongs to either group A (drug A) and group B (drug B), till all
      80 samples have been collected. After completion of the study, the researcher is informed
      which drug was labelled as 'Drug A' and 'Drug B' respectively.

      Study Protocol In the operating room, the patient was put under routine monitoring for
      general anaesthesia, including non-invasive blood pressure, electrocardiography, pulse
      oxymetry, end tidal carbon dioxide. The TOF Watch Sx, was also placed at the patients hand
      appropriately along the ulnar groove to monitor the neurotransmission activity of ulnar nerve
      . TOF reading was not taken at this time.

      Paediatric Bispectral Index (BIS) monitoring was also placed on the patient's forehead, to
      ensure the patient was adequately induced prior to any painful stimulation for example
      intravenous access placement or TOF monitoring.

      The patient was induced via sevoflurane gaseous induction, with a fresh gas flow rate of 8
      litres per min of oxygen. Sevoflurane was dialled between 4 to 6 percent, to ensure
      hemodynamic parameters were within acceptable range, and BIS count achieved was 40-50.

      Once the patient was fully relaxed and induced, a good functioning appropriate sized
      peripheral intravenous access was obtained.

      2 mcg/kg of fentanyl was given for analgesia. After administration of fentanyl, the TOF Watch
      Sx was calibrated and a baseline TOF reading was taken and recorded.The patient was paralyzed
      with 0.6 mg/kg of rocuronium, and intubation of the trachea was done once TOF count was less
      than 1.

      TOF monitoring was assessed at 15 minute intervals once patient was under general
      anaesthesia. Boluses of intravenous rocuronium 0.2 mg/kg was administered intermittently to
      maintain a TOF count of 2-3.

      The baseline haemodynamic values (blood pressure, heart rate, pulse oxymetry, end tidal
      carbon dioxide) were documented prior to induction, post-intubation and the subsequent 15
      minutes interval, to obtain a baseline and mean reading. The TOF readings were documented
      prior to Rocuronium administration (post-induction), post-intubation, then every 15 minutes
      interval, and just prior to reversal.

      All patients were given suppositories paracetamol 20-30mg/kg for analgesia. No further
      opioids were served other than on induction. Where applicable, regional blocks or local
      infiltration at the surgical site were given for analgesia.

      Prior to administration of the reversal agent as determined by randomization, it was ensured
      that the TOF reading was 2-3.

      The following time was taken and recorded :

        -  from administration of reversal agent to TOF ratio more than 0.9

        -  from administration of reversal to spontaneous ventilation

        -  from administration of reversal to adequate ventilation (tidal volume at least 6mls/kg
           and adequate respiratory rate for age)

        -  from administration of reversal to extubation The haemodynamic parameters (blood
           pressure, heart rate, pulse oxymetry, respiratory rate, tidal volume, end tidal carbon
           dioxide) were documented in 5 minute intervals upon administration of the reversal
           agent.

      Haemodynamic parameters in the recovery bay (blood pressure, heart rate, pulse oxymetry,
      respiratory rate) were also documented.

      Patients were also observed for any complications or side effects post-extubation such as
      nausea, vomiting, secretions, respiratory distress, etc in the recovery bay.
    

Intervention name(s): Neostigmine; Sugammadex Sodium
Intervention type(s): Drug; Drug
Intervention description(s): The TOF Watch Sx, and Paediatric Bispectral Index (BIS) monitoring were put on patient. Gaseous induction, with oxygen and Sevoflurane was given until BIS was 40-50, then a intravenous line was obtained. 2 mcg/kg of fentanyl was given for analgesia. then,the TOF Watch Sx was calibrated.The patient was paralyzed with 0.6mg/kg of rocuronium, and intubation of the trachea was done once TOF count was less than 1. A maintenance of 0.2 mg/kg of Rocuronium was given boluses every 30 minutes to maintain TOF count between 2-3. At the end of surgery, TOF count was checked to ensure it was between 2-3. Then a reversal dose for TOF count of 2 to 3 was 0.05 mg/kg of Neostigmine with 0.02 mg/kg of Atropine. Therefore the volume would be 0.2 mls per kg is to be administered.; The TOF Watch Sx, and Paediatric Bispectral Index (BIS) monitoring were put on patient. Gaseous induction, with oxygen and Sevoflurane was given until BIS was 40-50, then a intravenous line was obtained. 2 mcg/kg of fentanyl was given for analgesia. then,the TOF was calibrated.The patient was paralyzed with 0.6mg/kg of rocuronium, and intubation of the trachea was done once TOF count was less than 1. A maintenance of 0.2 mg/kg of Rocuronium was given boluses every 30 minutes to maintain TOF count between 2-3. At the end of surgery, TOF count was checked to ensure it between 2-3. Then the dose for reversal of sugammadex with a TOF count of 2 or 3 would be 2 mg/kg. This will also be equivalent to a volume of 0.2 mls per kg and given at the end of surgery.
Other intervention name(s): Prostigmine; Bridion
Intervention MeSH terms: Neostigmine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Paediatric general anaesthesia; Rocuronium; Neostigmine; Sugammadex