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Trial registered on ANZCTR


Registration number
ACTRN12617001505392
Ethics application status
Approved
Date submitted
18/10/2017
Date registered
25/10/2017
Date last updated
25/10/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Administration of clinical doses of neostigmine, commonly used in anaesthesia, and assessment of its effects on muscle strength, using a dynamometer, in healthy awake volunteers.
Scientific title
Do clinical doses of neostigmine induce muscle weakness, when administered to awake volunteers, in the absence of exposure to any non-depolarising neuromuscular blocking agents and if so does this have features of depolarising or non-depolarising blockade?

Secondary ID [1] 293167 0
None
Universal Trial Number (UTN)
U1111-1203-9278
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neostigmine induced muscle weakness in awake volunteers 305149 0
Condition category
Condition code
Anaesthesiology 304475 304475 0 0
Anaesthetics
Neurological 304476 304476 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Neostigmine 2.5 mg and glycopyrrolate 450 micrograms administered intravenously to awake volunteers and this dose repeated again at 15 minutes from the time of the initial dose.
Intervention code [1] 299416 0
Treatment: Drugs
Comparator / control treatment
Control group will receive intravenous normal saline 2 mls and this will be repeated at 15 minutes.
Control group
Placebo

Outcomes
Primary outcome [1] 303707 0
The maximum % change in hand grip strength (measured with a dynamometer) from baseline.
Timepoint [1] 303707 0
Maximum % change in hand grip strength observed during the 30 minute time interval after the initial neostigmine administration. This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [1] 339921 0
Maximum % change in Train of four ratio measured using electromyography at the first dorsal interosseous muscle following supra maximal stimulation of the ulnar nerve.
Timepoint [1] 339921 0
Maximum % change in train of four ratio observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [2] 339922 0
Maximum % change in single twitch height measured using electromyography at the first dorsal interosseous muscle following supra maximal stimulation of the ulnar nerve.
Timepoint [2] 339922 0
Maximum % change observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [3] 339923 0
Maximum % change in forced vital capacity (FVC) measured with ultrasonic spirometry.
Timepoint [3] 339923 0
Maximum % change in forced vital capacity (FVC)observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [4] 339924 0
Maximum % change in forced expiratory volume in one second (FEV1) measured with ultrasonic spirometry.
Timepoint [4] 339924 0
Maximum % change in forced expiratory volume in one second (FEV1) observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [5] 339925 0
Maximum change in FEV1/FVC ratio.
Timepoint [5] 339925 0
Maximum % change in FEV1/FVC ratio observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [6] 339926 0
Maximum % change in oxygen saturation
Timepoint [6] 339926 0
Maximum % change oxygen saturation observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [7] 339927 0
Maximum % change in heart rate.
Timepoint [7] 339927 0
Maximum % change in heart rate observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [8] 339928 0
Maximum % change in blood pressure.
Timepoint [8] 339928 0
Maximum % change in blood pressure observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [9] 339929 0
Dysphagia:

Dysphagia was assessed by asking if the patients were able to swallow. If able they were then given a sip of water and monitored for any choking, coughing or swallowing difficulty.
Timepoint [9] 339929 0
Dysphagia observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [10] 339930 0
Diplopia:
Diplopia assessment was carried out by asking the patient to look straight ahead and follow
a target as the examiner drew an ‘H’ shape. The target was kept 50cm away from the
patient to avoid convergence. Participants were asked if they experienced any double
vision.
Timepoint [10] 339930 0
Presence or absence of diplopia observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [11] 339931 0
Tongue depressor test for masseter strength.
Timepoint [11] 339931 0
The ability to retain tongue depressor during attempted removal was observed during the 30 minute time interval after the initial neostigmine administration.This measurement is recorded each five minutes for 30 minutes.
Secondary outcome [12] 339932 0
Symptoms or signs of muscle weakness observed by researcher or reported by volunteer.
Timepoint [12] 339932 0
Any symptoms or signs observed or reported during the 30 minute time interval after the initial neostigmine administration.
Secondary outcome [13] 339933 0
Gastrointestinal symptoms or signs noted by researcher or reported by the volunteer.
Timepoint [13] 339933 0
Any symptoms or signs observed or reported during the 30 minute time interval after the initial neostigmine administration.

Eligibility
Key inclusion criteria
We recruited healthy volunteers with American Society of Anesthesiologists (ASA) class I physical status to participate in the study.
Minimum age
18 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Pregnancy, history of neuromuscular or respiratory disease, or any condition that may interfere from the conduct of the study, such as allergy to the study medications or adhesive gel electrodes, currently taking any medication that may affect neuromuscular or respiratory function, or interfere with the study medications. ASA status equal to or greater than 2,

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The allocation was concealed in opaque sequentially numbered envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization sequence was generated by computer with a 2:1 allocation ratio for NG: Placebo groups and block size 3.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety
Statistical methods / analysis
Sample Size Determination:
Assumed the Neostigmine/Glycopyrrolate group would have a 20% mean reduction in the primary outcome from baseline (standard deviation (SD) 20%) while the Placebo group would have a 0% mean change (SD 5%), a sample size of 21 participants with 14 in the Neostigmine/Glycopyrrolate group and 7 in the Placebo group would be sufficient to detect a difference of 20% between the study groups using a two-sided t test with 80% power and a 5% significance level. Sample size calculation was done using G*Power (software version 3.1, Heinrich Heine University Düsseldorf, Düsseldorf, Germany).
A 2:1 allocation ratio was selected after balancing considerations of reduced statistical power as the result of unequal allocation and increased opportunity to make quantitative and qualitative observations on the potential effects of neostigmine administration in awake volunteers.

Baseline characteristics were compared using the t test for continuous variables or the Chi-squared test for categorical variables. A hierarchical test procedure was applied to the analysis of quantitative primary and secondary outcomes. Initially repeated measures ANOVA was used to compare changes from baseline over the 30-minute study period. The maximal percentage change from baseline observed during the 30-minute study period in the Neostigmine/Glycopyrrolate group was then compared to the change in Placebo group at same time point using the t test only if repeated measures ANOVA found a significant difference. This would avoid unnecessary multiple testing at each 5-minute time interval. A conservative significance level of 0.01 was applied to all statistical tests to accommodate multiple comparisons.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9205 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [2] 9206 0
Wollongong Hospital - Wollongong
Recruitment postcode(s) [1] 17859 0
2076 - Wahroonga
Recruitment postcode(s) [2] 17860 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 297785 0
Hospital
Name [1] 297785 0
Sydney Adventist Hospital Wahroonga
Address [1] 297785 0
185 Fox Valley Rd,
Wahroonga, NSW , 2076
Country [1] 297785 0
Australia
Funding source category [2] 297796 0
Charities/Societies/Foundations
Name [2] 297796 0
Australian Society of Anaesthetists - Jackson Rees Grant
Address [2] 297796 0
8/121 Walker St, North Sydney NSW 2060
Country [2] 297796 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Australian Society of Anaesthetists
Address
8/121 Walker St, North Sydney NSW 2060
Country
Australia
Secondary sponsor category [1] 296821 0
Hospital
Name [1] 296821 0
Sydney Adventist Hospital
Address [1] 296821 0
185 Fox Valley Rd,
Wahroonga, NSW , 2076
Country [1] 296821 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298843 0
University of Wollongong Human Research Ethics Committee
Ethics committee address [1] 298843 0
Northfields Ave
Wollongong NSW 2522
Australia
University of Wollongong Human Research Ethics Committee (HREC/13/WGONG/157),
Ethics committee country [1] 298843 0
Australia
Date submitted for ethics approval [1] 298843 0
04/01/2014
Approval date [1] 298843 0
06/02/2015
Ethics approval number [1] 298843 0
HREC/13/WGONG/157

Summary
Brief summary
Neostigmine is an anticholinesterase agent that is commonly used in anesthesia to reverse non-depolarizing neuromuscular blocking agents (NMBA). It is used to improve the rate of recovery from moderate non-depolarizing neuromuscular blockade and reduce the incidence of residual blockade. Neostigmine increases acetylcholine levels at the neuromuscular junction by inhibiting the breakdown of acetylcholine (Ach), which competitively antagonizes the NMBA. Neostigmine also acts at muscarinic sites leading to unwanted cholinergic side effects. Therefore the anti-muscarinic agents glycopyrrolate or atropine are administered in conjunction with neostigmine to reduce the severity of the effects.
Clinical doses of neostigmine have been reported to cause muscle weakness when administered after full recovery from blockade. However, these reports are potentially confounded by the presence of other anesthetic agents also known to influence neuromuscular blockade.Without the use of quantitative neuromuscular function monitoring, patients who have spontaneously recovered from NMBAs may be given neostigmine unnecessarily.
The primary aim of this study is to determine if clinical doses of neostigmine administered to healthy, unanesthetized volunteers would cause muscle weakness and impair respiratory function. We sought to define the size of the effect with hand grip strength, electromyography and spirometry. The secondary aim was to record the signs and symptoms experienced by the participants.
Trial website
Trial related presentations / publications
NONE
Public notes
Stewart, P., Liang, S., Li, Q., Huang, M., Bilgin, A., Kim, D.,
Phillips, S. (2016). The Impact of Residual Neuromuscular
Blockade, Oversedation, and Hypothermia on Adverse
Respiratory Events in a Postanesthetic Care Unit: A Prospective
Study of Prevalence, Predictors, and Outcomes. Anesthesia and
Analgesia, 123(4), 859-868. <a

Contacts
Principal investigator
Name 78418 0
A/Prof Paul Anthony Stewart
Address 78418 0
Clinical Associate Professor
Sydney Medical School
The University of Sydney.
Sydney Adventist Hospital Clinical School
PO Box 82
Wahroonga, NSW, 2076
Country 78418 0
Australia
Phone 78418 0
+61294874310
Fax 78418 0
Email 78418 0
paul.stewart@sah.org.au
Contact person for public queries
Name 78419 0
A/Prof Paul Anthony Stewart
Address 78419 0
Clinical Associate Professor
Sydney Medical School
The University of Sydney.
Sydney Adventist Hospital Clinical SchoolPO Box 82
Wahroonga, NSW, 2076
Country 78419 0
Australia
Phone 78419 0
+61294874310
Fax 78419 0
Email 78419 0
paul.stewart@sah.org.au
Contact person for scientific queries
Name 78420 0
A/Prof Paul Anthony Stewart
Address 78420 0
Clinical Associate Professor
Sydney Medical School
The University of Sydney.
Sydney Adventist Hospital Clinical SchoolPO Box 82
Wahroonga, NSW, 2076
Country 78420 0
Australia
Phone 78420 0
+61294874310
Fax 78420 0
Email 78420 0
paul.stewart@sah.org.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 48 0
Kent, N. B., Liang, S. S., Phillips, S. , Smith, N. A., Khandkar, C. , Eikermann, M. and Stewart, P. A. (2018), Therapeutic doses of neostigmine, depolarising neuromuscular blockade and muscle weakness in awake volunteers: a double-blind, placebo-controlled, randomised volunteer study. Anaesthesia, 73: 1079-1089. doi:10.1111/anae.14386
Attachments [1] 48 0
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary