Optimal Dose of Combination of Rocuronium and Cisatracurium (CRC)

January 31, 2018 updated by: Wooyoung Park, Yonsei University

Optimal Dose of Combination of Rocuronium and Cisatracurium: A Randomized Double-blinded Clinical Trial

BACKGROUND: The combinations of rocuronium and cisatracurium have a synergic effect. The investigators studied whether the prediction is possible to have a sufficient effect of reducing the dose when combining the two neuromuscular blocking agents through monitoring neuromuscular relaxation during surgery.

METHODS: Each group were intubating dose group (Group I, n=27) combined Effective Dose (ED)95 rocuronium and ED95 cisatracurium, small amount reducing group (Group S, n=27) reduced 10% of each ED95 and large amount reducing group (Group L, n=27) reduced 20% of each ED95. Before patients arrived in the operating room, rocuronium and cisatracurium were prepared by a nurse who was not involved in this study. Each study drug was administrated to the patient and timer was started with TOF-Watch® monitoring. Train-of-four (TOF) of the ulnar nerve was used as setting of 2 Hz per 12 sec. The investigators checked time to TOF ratio=0 (Onset), time to 1st TOF ratio>25% (Duration 25%) and TOF 25-75% (recovery index) under total i.v. anesthesia (TIVA). One way ANOVA was used for statistical analysis (α=0.05, β=0.2).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Introduction:

Rocuronium and cisatracurium are representative neuromuscular blocking agents used widely because the former have features of fast onset of peak effect and short duration of muscle relaxation relatively while the latter have comparatively long duration relaxation time and break down by Hofmann elimination and ester hydrolysis. A combination of the two have a synergic effect may be also used with either the priming method for rapid sequence intubation. It would contribute both to determine the effective combination rate clinically and to predict the pharmacokinetic characteristics that determine how much the synergistic effect of this combination. The investigators studied whether the prediction is possible to have a sufficient effect of reducing the dose when combining the two muscle relaxants through monitoring muscle relaxation during surgery.

Materials and methods:

This study was conducted to 81 patients scheduled for elective mastoidectomy and tympanoplasty after obtaining written informed consent. All patients included the American Society of Anesthesiologists (ASA) physical status I-II, aged 20-60, BMI 20-30 kg/m2. The exclusion criteria were as follows: a history of allergy to the study drugs, neuromuscular disease, pregnancy or breast-feeding, preoperative medication of antipsychotics or neuroleptics known to interact with non-depolarizing neuromuscular blocking agents (NMBAs), serum creatinine level>1.2 mg/dL, liver transaminase>40 U/L. Anthropometric variables such as height, weight were measured in ward before surgery. BMI calculated as total body weight divided by the squared height. Ideal body weight (IBW) was calculated by the formula of Devine {50 kg + 2.3 × (height [inch]-60) for man and 45.5 kg + 2.3 × (height [inch]-60) for woman} and used to administrate NMBAs of initial dose. Lean body weight (LBW) was calculated by the formula of James {LBW (men) = (1.10 × Weight(kg)) - 128 × ( Weight2 / (100 × Height(m))2), (women) = (1.07 × Weight(kg)) - 148 × ( Weight2 / (100 × Height(m))2)}. Additive dose of NMBAs was administrated by LBW. Patients were randomly assigned to each group by opening of sealed allocation envelope. Each group were intubating dose group (Group I, n=27) combined ED95 rocuronium and ED95 cisatracurium, small amount reducing group (Group S, n=27) reduced 10% of each ED95 and large amount reducing group (Group L, n=27) reduced 20% of each ED95.

Monitoring and Medication:

In the operating room, monitoring was accomplished to patients with a noninvasive blood pressure, pulse oximetry, electrocardiography, thermometer, Bispectral Index (BIS VISTA Monitoring System; Aspect Medical Systems Inc, Norwood, MA, USA), and T1/T4 ratio used TOF-Watch® (Organon, Teknica B.V., Boxtel, the Netherlands). Every 5 min, measured things are recorded.

Premedications with midazolam 2 mg and glycopyrrolate 0.2 mg were administrated to patients intramuscularly 1 h before surgery. Before patients arrived in the operating room, rocuronium and cisatracurium were prepared by a nurse who was not involved in this study. The syringe containing each study drug was conveyed to the performer of this study as the status of shielding the scale. The syringes of rocuronium and cisatracurium used each other syringe. Anesthesia was induced with propofol 1.5-2.5 mg/kg, remifentanil 0.4-0.6 mcg/kg, afterward maintained with target controlled infusion (TCI) of propofol 5-10 mg/kg/hr and remifentanil 0.05-2 mcg/kg/min. The infusion pump (Orchestra Module DPS, Fresenius-Vial, Brezins, France) was operated with Minto's and Marshall's pharmacokinetic model for effect site TCI of remifentanil and propofol.

The opposite arm against operation side was used for neuromuscular monitoring and attached to armboard of TOF-Watch®. Each study drug was administrated to the patient and timer was started with T1/T4 ratio monitoring. The surface electrodes of ulnar nerve placed at the wrist and Train-of-four (TOF) stimulation was used as setting of supramaximal square wave impulses with 200μs duration, 2 Hz per 12sec. The investigators checked times to TOF ratio=0 (Onset), 1st TOF ratio>25% (Duration 25%) and TOF 25-75% (Recovery Index), recovery time of 90% (TOF 25-90%) under total i.v. anesthesia (TIVA). Also the investigators checked the rate of additional rescue dose administrated with 10% of initial NMBAs dose, operation time from incision to surgical wound dressing, anesthesia time from entering to going out the operation room. Body temperature was maintained above 35°C using warm air blanket. The arterial pressure cuff was placed on the opposite arm against TOF monitoring.

Adverse Events and Management:

In all patients, anesthesia level was assessed based on a BIS score of 40-60. Moderate hypertension (>120% of baseline) or hypotension (<80% of baseline) was treated by increasing or decreasing rate of propofol infusion with fluid supplement. Severe hemodynamic change (systolic pressure < 90 mmHg or > 200 mmHg) was controlled by intravenous (IV) administration of phenylephrine 50 mcg or nicardipine 250 mcg repeatedly until being hemodynamic stable status. Unexpectedly, when hiccup or self-contained respiration was showed, additional rescue dose of NMBAs was administrated to the patient even though T1/T4 ratio was lower than 25%.

Statistical Analysis:

All data are expressed as means ± standard deviations (SDs), numbers (percentages), or medians (upper and lower quartiles), as appropriate. Data between the groups were compared using the χ2 test, Fisher exact test, independent t test, or the Mann-Whitney U test, as appropriate. To assess data normality, the Kolmogorov-Smirnov test was performed on the data set. According to a preliminary study, 24 patients would be required in each group with a power of 0.9 and a type I error of 0.05. Factoring in a drop-out rate of 10%, the investigators calculated that 27 patients would be required for each group. All statistical analyses were performed with the SPSS 18.0 (SPSS Inc., Chicago, IL, USA) program. A P value <0.05 was considered statistically significant.

Study Type

Interventional

Enrollment (Actual)

81

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 56 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • the American Society of Anesthesiologists (ASA) physical status I-II
  • BMI 20-30 kg/m2
  • Patients scheduled for mastoidectomy and tympanoplasty.

Exclusion Criteria:

  • a history of allergy to the study drugs,
  • neuromuscular disease,
  • pregnancy
  • breast-feeding,
  • preoperative medication of antipsychotics or neuroleptics known to interact with NMBAs
  • serum creatinine level>1.2 mg/dL,
  • liver transaminase>40 U/L.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Intubating dose, Group I

combined ED95 rocuronium and ED95 cisatracurium

ED95, dose causing on average 95% suppression of neuromuscular response.
Experimental: 10% reduction of combination of Esmeron® and Nimbex®, Group S
This arm reduced 10% of combined ED95 rocuronium and ED95 cisatracurium
Drug: 10% reduction of combination of Esmeron® and Nimbex®
Patients were randomly assigned to each group by opening of sealed allocation envelope. After collection of data, allocation number was matched with each group. The participants matched at Group S were administered with NMBAs reduced 10% of each ED95. Before patients arrived in the operating room, rocuronium and cisatracurium were prepared by a nurse who was not involved in this study. Each drug dosage was determined by allocation number. The syringe containing each study drug was conveyed to the performer of this study as the status of shielding the scale. The syringes of rocuronium and cisatracurium used each other syringe.
Other Names:
  • Esmeron®, 74119419, ATC code:M03AC09
  • Nimbex®, 74500213, ATC code:M03AC11
Experimental: 20% reduction of combination of Esmeron® and Nimbex®, Group L
This arm reduced 20% of combined ED95 rocuronium and ED95 cisatracurium
Drug: 20% reduction of combination of Esmeron® and Nimbex®
The participants matched at Group L were administered with NMBAs reduced 20% of each ED95.
Other Names:
  • Esmeron®, 74119419, ATC code:M03AC09
  • Nimbex®, 74500213, ATC code:M03AC11

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Onset of Neuromuscular Blocking Agents(NMBAs)
Time Frame: Intraoperative, an average of 5 minutes
Time from administration of initial NMBAs to Train-of-four (TOF) ratio=0, assessed up to 15 minutes during general anesthesia.
Intraoperative, an average of 5 minutes
Duration 25% of Neuromuscular Blocking Agents(NMBAs)
Time Frame: Intraoperative, an average of 1 hours
Time from administration of initial NMBAs to Train-of-four (TOF) ratio >25%, assessed up to 2 hours during general anesthesia.
Intraoperative, an average of 1 hours
Recovery Index of Neuromuscular Blocking Agents(NMBAs)
Time Frame: Intraoperative, an average of 20 minutes
Time from TOF ratio 25% to 75%, assessed up to 1 hour during general anesthesia.
Intraoperative, an average of 20 minutes

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Operation Time
Time Frame: Intraoperative, an average of 3 hours.
Time from skin incision to wound dressing assessed up to 8 hours.
Intraoperative, an average of 3 hours.
Anesthetic Time
Time Frame: Intraoperative, an average 4 hours.
Time from induction to recovery of anesthesia, asessed up to 3 hours.
Intraoperative, an average 4 hours.
Additional Rescue Doses Per Hour Ratio.
Time Frame: Intraoperative, an average of 3 hours.
Additional Rescue Doses Per Hour Ratio is the number per hour of addition of rescue dose administrated with 10% of initial NMBAs dose. The formula is {(Addition number + 1 / Anesthetic time) x 60}.
Intraoperative, an average of 3 hours.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non Invasive Blood Pressure,
Time Frame: Before and after induction of anesthesia, an average 10 min.

Before induction of anesthesia, non invasive blood pressure was measured for baseline.

And after injection of NMBAs, non invasive blood pressure was measured at 10 min.
Before and after induction of anesthesia, an average 10 min.
Peripheral Oxygen Saturation
Time Frame: Before and after induction of anesthesia, an average 10 min.

Before induction of anesthesia, peripheral oxygen saturation was measured for baseline.

And after injection of NMBAs, peripheral oxygen saturation was measured at 10 min.
Before and after induction of anesthesia, an average 10 min.
Body Temperature
Time Frame: Before and after induction of anesthesia, an average 10 min.

Before induction of anesthesia, body temperature was measured for baseline by oral temperature probe.

And after injection of NMBAs, non invasive blood pressure was measured at 10 min by esophageal temperature probe.
Before and after induction of anesthesia, an average 10 min.
Bispectral Index
Time Frame: Before and after induction of anesthesia, an average 10 min.

The BIS monitor provides a single dimensionless number, which ranges from 0 (equivalent to EEG silence) to 100. A BIS value between 40 and 60 indicates an appropriate level for general anesthesia, as recommended by the manufacturer.

Before induction of anesthesia, bispectral index was measured for baseline. And after injection of NMBAs, bispectral index was measured at 10 min.
Before and after induction of anesthesia, an average 10 min.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yonsei University

Investigators

  • Study Director: Young Gwan Cheon, Institutional Review Board of Wonju Severance Christian Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2014

Primary Completion (Actual)

February 1, 2015

Study Completion (Actual)

February 1, 2015

Study Registration Dates

First Submitted

June 4, 2015

First Submitted That Met QC Criteria

July 10, 2015

First Posted (Estimate)

July 13, 2015

Study Record Updates

Last Update Posted (Actual)

March 2, 2018

Last Update Submitted That Met QC Criteria

January 31, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • combination P-1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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