An Observational Study of Rocuronium 0.6 mg/kg Comparing Onset Time, Duration of Action and Effect on Intubation Conditions in Younger (18 - 40 Years) and Elderly Patients (> 80 Years)
Conditions: Elective Surgery
Sponsor: Rigshospitalet, Denmark

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Neuromuscular blocking agents in the elderly  
 
Protocol 
An observational study of rocuronium 0.6 mg/kg comparing onset time, duration 
of action and effect on intubating conditions in younger (18 – 40 years) and elderly 
patients (> 80 years)  
Version 1, December 6th 2018 
 
Principal investigator 
Matias Vested, MD, PhD 
Department of Anaesthesia, Centre of Head and Orthopedics, 4031 Rigshospitalet,  
University of Copenhagen, Denmark 
 
Sponsor 
Lars Rasmussen, MD, PhD, DMSc  
Department of Anaesthesia, Centre of Head and Orthopedics, 4031 Rigshospitalet,  
University of Copenhagen, Denmark 
 
 
Responsible department: 
Department of Anaesthesia, Centre of Head and Orthopedics, 4031 Rigshospitalet,  
University of Copenhagen, Denmark 
 
 
 

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Background 
The number of elderly patients (>80 years) is increasing and a large proportion of these patients 
will require surgery and anesthesia within the next decades1. Elderly patients are at higher risk of 
major morbidity and mortality2 and are characterized by a reduction in cardiac output, liver 
function and renal function. These physiological changes influence pharmacodynamics and 
pharmacokinetics of drugs administered during anesthesia as for example neuromuscular blocking 
agents (NMBA).  
During anesthesia NMBAs are used to facilitate tracheal intubation, establish muscle relaxation 
and suppress reflexes during surgery3–5. Elderly patients are more sensitive towards muscle 
relaxants. In addition studies have reported prolonged duration of NMBAs6–8 and an observational 
study found that elderly patients are more prone to experience residual neuromuscular blockade 
in the post anesthesia care unit9. However, most studies have been conducted in elderly below 80 
years7,10.  
It is unknown if there are differences in onset times of NMBAs e.g. rocuronium, mivacurium and 
cisatracurium between younger patients and elderly. Onset time for NMBAs in the elderly is of 
importance since it may influence intubating conditions, especially during rapid sequence 
induction. For example it is unknown in the elderly if an increased dose of NMBA reduces the 
onset time. There remains a need for studies investigating the optimal dose for facilitating 
intubation in the elderly, both during rapid sequence induction and during elective procedures.  
The aim of this study is to determine the onset time, duration of action and effect on intubating 
conditions for rocuronium 0.6 mg/kg in patients aged 18-40 years and in patients with age > 80 
years. The hypothesis of this study is that rocuronium administered in elderly patients (>80 years) 
has a longer onset in the elderly compared to younger patients.  
 
 
 

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Method:   
Design:  
Observational clinical study 
Outcomes: 
The primary end point is onset time, defined as the time from the end of rocuronium injection to 
Train-of-four (TOF) count of 0 monitored by acceleromyography.  
The secondary endpoints are intubating conditions rated by an intubating difficulty scale11 after 90 
seconds and duration of action, defined as time from end of rocuronium injection to reappearance 
of TOF ratio > 0.9.    
The pharmacodynamic data obtained are: time to reappearance of the T1, time to T1 recovery to 
25% (of the final T1), and time to TOF ratio 0.90 
 
Number of patients: 32 patients (16 in each group): 
Group young: 16 patients receiving rocuronium 0.6 mg/kg 
Group elderly: 16 patients receiving rocuronium 0.6 mg/kg 
Doses are based on ideal body weight, calculated as height (cm) minus 105 for women and height 
(cm) minus 100 for men.  
Inclusion criteria: 
Patients > 18 years old  
Informed consent 
Scheduled for elective surgery (>1 hour) under general anaesthesia with intubation and use of 
rocuronium  

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American Society of Anesthesiologists (ASA) physical status classification I to III 
Can read and understand Danish  
Exclusion criteria: 
Known allergy to rocuronium 
Neuromuscular disease that may interfere with neuromuscular data 
Indication for rapid sequence induction 
End of study: 
When 32 patients have been evaluated considering the primary endpoint the study is concluded.  
 
Pre-operative assessment: 
In the Case Report Form (CRF) the following baseline data is noted: 
Age 
Sex 
Weight 
Height 
BMI 
ASA group (I-IV) 
Co-morbidity  
 
 
 

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Perioperative treatment: 
Monitoring: 
The patient will be monitored with ECG, noninvasive blood pressure, oxygen saturation, and 
temperature sensors in nose cavity or bladder. Neuromuscular monitoring will be performed with 
TOF-Watch SX connected to a computer for collection of neuromuscular data (Version 2.5 INT 
2007, Organon, The Netherlands). The monitoring will be done according to international 
guidelines13. TOF-Watch SX will be placed on the arm, where there is the least monitoring in 
general. Initially, the skin will be shaved and cleansed and rubbed with an abrasive. Small ECG 
electrodes will be used. They will be placed on the wrist over the ulnar nerve. The acceleration 
transducer will be placed on the thumb and attached in the associated hand adaptor. When the 
patient is adequately anesthetized we will start the TOF Watch SX and give two train-of-four (TOF) 
nerve stimulations followed by a tetanic stimulation with 50 Hz for 5 seconds. Then we will 
calibrate the TOF Watch SX with the CAL2 button and start the TOF mode and measure the TOF (2 
Hz for 1.5 seconds) each 15 sec. After securing a stable signal with less than 5% deviation for two 
minutes we will inject rocuronium. When TOF = 0 we will measure the PTC for every 3-4 minutes.  
An intravenous catheter will be placed in the opposite hand.  
 
Anesthesia: 
General anesthesia comprises induction with propofol 1-2 mg/kg and fentanyl 1.5-3.0 mcg/kg. 
Tracheal intubation is performed 90 seconds after administration of rocuronium 0.6 mg/kg. 
Anesthesia will be maintained with propofol approximately 5 mg/kg/hour and remifentanil 0.25-
0.5 mcg/kg/min and adjusted according to depth of anesthesia.  
 
Treatment values:  
Blood pressure: Mean arterial pressure (MAP) max. 30 % difference from baseline.  

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Neuromuscular monitoring continues until TOF ≥ 0.90 and stable over 2 min. In case of TOF < 0.90 
at the end of surgery the NMB is reversed with neostigmine or sugammadex according to 
guidelines at the department. Subsequently, the patient is awakened and taken to the recovery 
room.  
Intubating conditions: 
Intubating conditions will be assessed 90 seconds after end of injection of rocuronium 0.6 mg/kg 
employing the Intubating Difficulty Scale. The scale comprises seven items: 
 
N1-The number of supplementary attempts, an attempt defined as one advancement of the tube 
in the direction of the glottis during direct laryngoscopy or one like advancement of the tube in 
the case of a blind intubation trial. 
N2-The number of supplementary operators; N2represents the number of additional persons 
directly attempting (i.e., not assisting) intubation. 
N3-The number of alternative techniques used. For example, changing from an oral intubation to 
blind nasotracheal intubation or from a curved blade to straight blade increases N3by 1 point. The 
various techniques used should be noted in chronological order, so that subsequent identification 
of techniques ineffective in a particular case (or series) may be undertaken. 
N4-Glottic exposure as defined by the Cormack grade [4 ] minus one; grade I (N4= 0) on this scale 
corresponds to complete visualization of the vocal cords, grade II (N4= 1) to visualization of the 
inferior portion of the glottis, grade III (N4= 2) to visualization of only the epiglottis, and grade IV 
(N4= 3) to a nonvisualized epiglottis. Glottic exposure is evaluated during the first attempt by the 
first operator. In case of successful intubation after blind nasotracheal intubation, N4= 0. If the 
blind attempt(s) fail, glottic exposure is evaluated during the first subsequent alternative 
visualized laryngoscopic attempt. 
N5-The lifting force applied during laryngoscopy; N5= 0 if little effort is necessary, and N5= 1 if 
subjectively increased lifting force is necessary. This notion is based on the operator's impression 
that an abnormal amount of force was used compared with routine practice. 

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N6-The necessity of applied external laryngeal pressure for optimized the glottic exposure; N6= 0 
if no external pressure is applied. N6= 1 if external laryngeal pressure is necessary. Application of 
the Sellick Maneuver is intended to inhibit aspiration of gastric contents and does not alter the 
score. 
N7-Position of vocal cords; N7= 0 if vocal cords are in abduction. N7= 1 if the vocal cords are in 
abduction, presenting an impediment to tube passage. If the vocal cords are not visualized, N7= 0 
by default. 
 
Positioning: 
The patient will be positioned with the arm with neuromuscular monitoring equipment in 
abducted position. It is ensured that the monitoring equipment is as unaffected as possible to 
achieve the most precise neuromuscular data. Intravenous cannula will be placed in opposite hand 
than neuromuscular monitoring equipment. 
 
Surgery: 
Surgery with use of rocuronium 0.6 mg/kg for intubation.  
Respiratory: 
Patients are oxygenated at FiO2=1.0 during preoxygenation and induction of anesthesia until the 
trachea is intubated. Anesthesia continues initially with FiO2=0.30. Patients are ventilated with 
Pressure Control Ventilation, tidal volume 7 ml/kg, PEEP (positive end-expiratory pressure) 5 cm 
H2O and respiration frequency 10-12 targeting normocapnia (ETCO2 at 4.5-5.5 kPa). If PaCO2> 6 
kPa primarily the respiration frequency (RF) will be increased. If hypoxemia arises, defined as 
SpO2< 95 or PaO2< 10 kPa primarily FiO2 will be increased. In the event of deficient effect, PEEP 
will be increased.   
Fluid therapy:  

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1000 ml Ringer lactate is given intraoperatively. Blood loss up to 500 ml is replaced with Ringer 
lactate 1:2.5. Blood loss in excess of this is replaced in accordance with the local guidelines. 
In case of hypotension ephedrine or phenylephrine will be administered. In case of need for 
continuous inotropic infusion phenylephrine or noradrenalin will be used.  
Antibiotics: 
According to local guidelines. Dose and name will be noted on the CRF. 
 
Pain treatment:  
Postoperative pain treatment with paracetamol, fentanyl, morphine and peripheral nerve blocks 
according to local guidelines.  
PONV treatment: 
PONV prophylaxis and treatment with ondansetron, dexamethasone and droperidol according to 
local guidelines.  
 
Data collection 
Perioperative data collection that will be noted in CRF: 
Type of operation with operation code 
TOF values (NMB sheet) 
Body temperature measured immediately after intubation and again immediately before 
extubation 
Intubating difficulty score   
Operating time (from incision to last suture) 
 

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Statistics: 
Normal distributed variables will be expressed by means and standard deviations; variables that 
are not normal distributed will be expressed by medians and interquartile ranges. Student´s t-test 
is used to compare normal distributed data and Mann-Whitney test to compare not normal 
distributed data.  
X2-test or Fisher´s exact test will be used for frequencies when comparing the two groups. 
 
Sample size: 
We estimated a 20 seconds standard deviation for onset time of rocuronium based on previous 
studies12. We considered a difference in onset time of 30 seconds between the younger and 
elderly groups to be clinically relevant. We have calculated that a sample size of 16 patients in 
each group will allow us to detect this difference, with 5% Type 1 error risk and 90% power.  
 
Schedule: 
Inclusion of 2-3 patients per week is expected corresponding to duration of inclusion of 
approximately 10-16 weeks. Inclusion: Planned to go on in the period from December 2018 to 
April 2019. Inclusion of patients will be stopped when the desired number of patients is achieved. 
The trial will be counted as concluded, when the last patient has registered with the primary 
endpoint.  
Data analysis and reporting: from April 2019 to June 2019. 
Risks and side effects 
Rocuronium: According to the product summary side effects are: 
Not common (0,1-1%): Hypotension, anafylactic reaction.  
Seldom (< 0,01%): Shock, angioedema, face edema. 

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Tracheal intubation with use of rocuronium is routinely performed at Department of Anaesthesia, 
Centre of Head and Orthopedics, 4031 Rigshospitalet. In both groups the patients will receive 
rocuronium in a dose aiming to provide optimal intubating conditions. It is not regarded as a 
disadvantage to use rocuronium, since the effect is monitored through surgery and if needed fully 
reversed by a reversal agent upon end of surgery. 
 
Ethical considerations:  
Tracheal intubation is as a standard performed with use of a rocuronium 0.6 mg/kg. Anesthesia 
and surgery will follow standard guidelines. The possible benefit in this trial is to investigate 
whether rocuronium 0.6 mg/kg has a different onset time in the elderly compared to younger 
patients. This may result in different intubating difficulty scores between younger and elderly 
patients.  The results may help to detect the optimal dose of rocuronium for intubation of the 
trachea in elderly patients.   
Consent and patient recruitment:  
Patients are recruited among those referred to the Department of Anaesthesia, Centre of Head 
and Orthopedics, 4031 Rigshospitalet who meet inclusion criteria and who have no exclusion 
criteria. 
The principal investigator is responsible for patient information and declaration of consent. In case 
the principal investigator is not able to interview the patient another investigator with GCP 
experience and medical knowledge within anaesthesia can perform the interview instead by 
referring to the principal investigator or sponsor. Written and oral patient information will be 
disclosed at the day of operation or 1-14 days before operation, during the preoperative 
anesthetic interview. This will be done in an undisturbed room.  The patient will be offered the 
possibility of being accompanied by a family member or another person at the information 
interview. The patient will be informed that he/she will receive usual treatment if he/she does not 
want to participate, and that participation is voluntary, and that he/she always has the right to 
disclaim consent without affecting the further treatment.  

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After a period of consideration, depending on the patient´s needs and maximum 30 minutes 
before operation, an attempt will be made to obtain consent. 
 
Informed consent will be obtained before the patients arrive to the operation ward. We thereby 
wish to avoid putting the patients in a situation where they in a stress-full environment at the 
operation ward have to decide about participation in the trial.   
The trial will be reported to the Scientific Ethics Committees, Danish Medicines Agency and Danish 
Data Protection Agency. The patients in the trial are assured access to receive further information 
about the trial through the principal investigator, who as contact person is referred to in the 
patient information. The “Forsøgspersoners rettigheder i et sundhedsvidenskabeligt 
forskningsprojekt (Rights of Trial Subjects)” published by the Scientific Ethics Committee will be 
provided. The trial will be considered as having started on the date when there is a signed 
declaration of consent from the first patient, who will thereby be considered as included. 
Conclusion of the study is when the last patient has been evaluated considering the primary 
outcome. At the end of the trial, investigator and sponsor will inform the Scientific Ethics 
Committee and the Danish Medicines Agency of this within 90 days. The trial will be registered in 
an international database (www.clinicaltrials.gov), before the recruitment of patients is started. 
Quality control: 
General procedures for quality control and quality assurance will be followed according to Good 
Clinical Practice guidelines.  
Access to patients´ journals 
Upon granting of informed consent, principal investigator, sponsor, a representative of sponsor or 
third parties are authorized access to the patients´ journal to find information regarding the 
patients´ health conditions that are relevant for the conduction of the trial.  
Data collection and storage: 

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Primary investigator will arrange for data collection and storage of CRFs in locked premises. Data 
will be stored for 5 years after conclusion of the trial. The information about the patients’ health 
conditions, other purely private circumstances and other information that arises in connection 
with the trial is covered by the obligation of confidentiality. The information about the patients is 
protected by the Act on processing of personal information and the Danish Health Act. 
 
 
Responsible department: 
Department of Anaesthesia, Centre of Head and Orthopedics, 4031 Rigshospitalet,  
University of Copenhagen, Denmark 
 
Publication: 
The results, either positive, negative or inconclusive, will be submitted for publication in an 
international, English-language journal. Authorship will occur in accordance with international 
Committee of Medical Journal Editors’ rules (the Vancouver Group). The right to data and know-
how that emerges in connection with the trial will belong to the trial coordinator and the 
Department of Anaesthesia, Centre of Head and Orthopedics, 4031 Rigshospitalet, University of 
Copenhagen, Denmark. 
 
Registration: 
The study will be registered at www.clinicaltrials.gov 
 
Economy:  
Principal investigator and sponsor have taken the initiative to this trial.  

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Expenses in the trial are covered by departmental sources and covers salary for study 
investigators.  
Patients participating in the trial will not receive financial compensation.  
Patients participating in this trial are covered by the insurance “Patienterstatningsordningen” and 
“Ordningen om erstatning for lægemiddelskader”.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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