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Trial registered on ANZCTR


Registration number
ACTRN12619000848101p
Ethics application status
Submitted, not yet approved
Date submitted
13/05/2019
Date registered
14/06/2019
Date last updated
14/06/2019
Date data sharing statement initially provided
14/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Can general anaesthesia provide similar results in the population in terms of pain after a total knee replacement surgery when compared to spinal anaesthesia?
Scientific title
General anaesthesia or neuraxial anaesthesia combined with adductor canal block and local infiltrative analgesia for total knee arthroplasties: A non-inferiority randomized controlled trial
Secondary ID [1] 298214 0
Nil
Universal Trial Number (UTN)
U1111-1233-3309
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Total knee replacement 312815 0
postoperative pain management 313027 0
Osteoarthritis 313028 0
Condition category
Condition code
Anaesthesiology 311312 311312 0 0
Anaesthetics
Anaesthesiology 311313 311313 0 0
Pain management
Musculoskeletal 311538 311538 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Common anaesthetic techniques used for total knee arthroplasty (TKA) include general anaesthesia (GA) and neuraxial anaesthesia (NA - Spinal anaesthesia). NA is the technique of choice in many centers since many consider it provides better analgesia compared to GA. However, this is debatable in the era of modern anaesthesia. In a number of recent studies, both GA and NA techniques have shown to be equally effective, providing similar outcomes in terms of mortality and complications. Today, anaesthetists have been performing regional blocks to promote better pain relief for knee replacements. Most commonly, the adductor canal block (ACB) is performed. Local infiltrative analgesia (LIA) by the surgeons also decreases pain. We believe that the addition on ACB to both GA or NA will provide great pain relief for patients and the choice of anaesthesia (GA or NA) does not influence the outcomes. Participants: patients with osteoarthritis undergoing TKA. Patients can go either to NA or GA group depending on the randomization. Both will receive ACB and LIA and we will measure opioid consumption in the postoperative period, patients satisfaction, pain scores, nausea and vomiting episodes and anaesthetic time for each technique.

Intervention
Anaesthesia and operative care

PREOPERATIVE
Assessment: All patients will be assessed prior to the anaesthetic procedure as per normal standard in our institution. This may happen at the pre-assessment clinic or prior to the procedure. The research will be explained to the patient and informed consent obtained if his/her decision is to be involved in the study.
Premedication: We usually do not give pre-medication to the patients in our institution. Anxiolytics may be given at the discretion of the anaesthetist. Midazolam as a 0.5mg incremental intravenous bolus doses will be accepted for this purpose.



INTRAOPERATIVE
Group NA: After inserting an intravenous cannula, patients will be positioned for the neuraxial procedure. Patients will be fully monitored according to the ANZCA (Australian and New Zealand College of Anaesthetists) recommendations. Anxiolytics may be given at the discretion of the anaesthetist. Midazolam as a 0.5mg incremental intravenous bolus doses will be accepted for this purpose.
Technique: Aseptic. The spinal needle will be inserted at the interspinal level 3 to 4 or 4 to 5 (L3-L4 or L4-L5 levels). A dose of 12.5 to 15 mg (3.0 mL) of Hyperbaric Bupivacaine 0.5% will be given in the intrathecal space. After the procedure is done and tested if working properly, ACB will be performed (explained below). During the procedure, patients will receive light sedation with target-controlled infusion (TCI) of propofol 10mg.mL (Alaris® PK syringe pump) intravenously titrated to effect (with initial target effect site concentration set at 0.5 µg ml-1, gradually altered by increments to a maximum of 3.0 µg ml-1) with supplemental oxygen.

Group GA: After inserting an intravenous cannula, patients will be positioned for GA. Patients will be fully monitored according to the ANZCA (Australian and New Zealand College of Anaesthetists) recommendations.
TCI of propofol (using Marsh or Schnider pharmacokinetic models depending on the anaesthetist preference with a minimum target effect site concentration set at 2.5 µg ml-1, gradually altered by increments to achieve a Bispectral index below 60) and remifentanil target control intravenously (Minto pharmacokinetic model) with maximum plasma concentration of 8 mcg/ml to avoid acute tolerance to opioids (Kim D. J Anesth. 2018 Dec;32(6):886-892).The depth of anaesthesia will be monitored using BIS (Bispectral index). This will be used for both induction and maintenance of anaesthesia. The airway device used during the procedure will be defined by the anaesthetist preference. Possibilities include Laryngeal Mask Airway (LMA) or endotracheal tubes. ACB will be performed after the airway is secured. The use of muscle relaxant will be by the discretion of the anaesthetist.

Local infiltration anaesthesia (LIA) by surgeons
Towards the end of surgery, all subjects will receive up to 150 ml of ropivacaine (0.2%) (Depending on patient’s weight) with ketorolac 30 mg and 0.5 mg of epinephrine infiltration of local anaesthetic in the perisurgical area. The mixture will be injected after insertion of the prosthesis using a systematic technique to ensure uniform delivery of local anaesthetic to all tissues incised, handled or instrumented during the procedure. 1/2 of the volume will be injected into the posterior joint capsule and both collateral ligaments. Infiltration sites included the posterior capsule and the intercondylar area, the anterior capsule, the collateral ligaments and along the femur and tibia. The remaining volume will injected along the borders of and into the capsule and cut quadriceps tendon, infra-patellar ligament, possible remnants of the fat pad, cruciate ligaments and soft tissues surrounding the joint and into the subcutaneous tissues before wound closure. Only surgeons with experience in LIA will be doing the injections.

For Both NA and GA groups:
All patients will receive in the surgical theatre by the intravenous route:
- Cephazolin 2 grams – Prior to the surgical incision
- Tranexamic acid 1g at the beginning of the operation. Another 1 g will be given in 2 hours after the first dose or it will be given by the surgeons depending on their preference
- Dexamethasone 8mg IV within 1 hour after the incision
- Ondasentron 4mg IV at the end of the procedure
- Paracetamol 2g for males and 1.5gr for females within 1 hour after the incision
- Parecoxib 40mg within 1 hour after the incision
- 10 mg of oxycodone at the end of the procedure (skin sutures)

Adductor Canal Block
This will be performed for all the patients in the research prior to the surgery starts. For the NA group, this will be done after the spinal procedure and for the GA group, this will be done after the patient is anaesthetized.
Procedure: At the midthigh level, approximately halfway between the superior anterior iliac spine and the patella, a dynamic scan with a high-frequency linear array transducer will used to identify the superficial femoral artery (SFA) deep to the medial third of the sartorius muscle in a transverse cross-sectional view. After identification of the appropriate location, experienced anaesthetists will inject local anaesthetic (20 mL of Ropivacaine 0.375% ) with a 22- gauge spinal needle using an in-plane ultrasound technique.

Local Anaesthetic Toxicity
A maximum dose of 3mg.Kg of Ropivacaine will be allowed to be used in a patient. This will be calculated by the sum of the doses given by surgeons and anaesthetists. In all procedures, surgeons will be informed the maximum volume they can use in the patient. A recent research showed that serum concentration of ropivacaine after LIA using 270 mg ropivacaine with and without an additional 100 mg perineural ropivacaine (ACB) remained well below the toxicity threshold of 3.0 µg/mL at all time points (Koniuch KL. Regional Anesthesia & Pain Medicine Published Online First: 11 January 2019. doi: 10.1136/rapm-2018-100043).


C. Postoperative
In the postoperative unit, ACB will be tested by an experienced anaesthetist for loss of sensation to cold in the saphenous area.

Post-operative prescribed analgesia and follow up:
- All patients are followed by the acute pain service (APS) in our hospital after any regional block. Therefore, all the participants in the research will have a similar treatment as any other patient would. The APS team follow up patients until they have adequate pain control with oral medications and the block has regressed completely. To assess our primary outcome, participants will have intravenous opioids for a minimum of 36 hours and therefore, the APS service will follow them all for a minimum period of 36 hours. Since the research follow up is only for 36h, the continuation of the APS for the participant will depend on the APS decision based on the above criteria.
Regular medications prescribed for all the patients during their entire length of stay in the hospital
- Oral ibuprofen 400 mg 8 hourly (First dose 12h after parecoxib)
- Oral acetaminophen 1g 6-hourly (First dose 6h after first dose)
Pro Re Nata (PRN) medications:
- Morphine PCA intravenously
Settings - Bolus: 1 mg; Lockout: 5 minutes Maximum dose per hour: 12 mg. Morphine PCA can be removed only after 36h after the patient arrives in the post-anaesthetic care unit (PACU). The maintenance of this medication or the decision to stop it and prescribe another one will be by the discretion of the APS team.
- Oral ondasentron 4 mg every 8 hours. This will be prescribed for all the patients during their entire length of stay in the hospital

Monitoring fidelity of intervention
All the intervention done in the perioperative period in our patients will be charted in their anaesthetic record as per usual practice. This will make easy to find if the intervention was followed properly during the patient’s study period.
Intervention code [1] 314452 0
Prevention
Intervention code [2] 314693 0
Treatment: Other
Comparator / control treatment
Control group: NA (neuraxial anaesthesia)
Comparator group: GA (general anaesthesia)
Control group
Active

Outcomes
Primary outcome [1] 320046 0
The primary outcome of this study is opioid consumption within the first 36 hours following surgery. This will be measured by the amount of morphine used in the PCA pump after 36h. Therefore, after 36 hours, we will analyze and collect the data of morphine consumption in the PCA pump.
Timepoint [1] 320046 0
36 hours after the surgery finished
Secondary outcome [1] 370354 0
1. Patient's satisfaction regarding the type of anaesthetic he had (GA or NA). This will be measured in a scale of zero to ten. Being 10 the maximum satisfaction possible.

Timepoint [1] 370354 0
Timepoint 1: This will be asked at the moment that the patient will be discharged.
Secondary outcome [2] 371069 0
2. Pain scores using the Visual Analogue Scale (VAS) 0 – 100 (VAS; 0 = no pain, 100 = worst pain imaginable).
Timepoint [2] 371069 0
Timepoint 2: This will be asked every 30 minutes until the patient goes to the ward. Than VAS scores will be measured every 8 hours but not between 08:00p.m to 08:00a.m. The last measurement will be at 36h after T0.
Secondary outcome [3] 371070 0
3. Time for the first rescue of opioid in PACU (if any). This information will be collected from the analysis of the PCA pump.

Timepoint [3] 371070 0
Timepoint 3: This information will be collected from the analysis of the PCA pump at 36h after T0.
Secondary outcome [4] 371071 0
4. Nausea episodes and severity using the Visual Analogue Scale (VAS) 0 – 100 (VAS; 0 = no nausea, 100 = worst nausea episodes).

Timepoint [4] 371071 0
Timepoint 4: This will be measured every 30 minutes until the patient goes to the ward. Than VAS scores will be measured every 8 hours but not between 08:00p.m to 08:00a.m. The last measurement will be at 36h after T0.
Secondary outcome [5] 371072 0
5. Theatre time - Time between patient's entrances in the operating theatre to PACU (post-anaesthetic care unit) entrance. This time will be collected from the electronic anaesthetic chart. The reason to measure this timeframe is to evaluate if the choice of anaesthesia will influence in theatre efficiency.

Timepoint [5] 371072 0
Timepoint 5: This data will be collected at 36h after T0.
Secondary outcome [6] 371073 0
6. PACU time - From the beginning to the end of PACU. The reason to measure this timeframe is to evaluate if the choice of anaesthesia will influence in PACU time. This time will be collected from the electronic PACU document
Timepoint [6] 371073 0
Timepoint 6: This data will be collected at 36h after T0.
Secondary outcome [7] 371074 0
7. Theatre time and PACU time. This time is the combination of both Theatre and PACU time.

Timepoint [7] 371074 0
Timepoint 7: This data will be collected at 36h after T0.
Secondary outcome [8] 371075 0
8. Length of stay – We will check daily when the patients are discharged home. We will count the days and hours of stay from the time that the patient was admitted in the hospital to the discharge time. This data will be collected from the electronic medical chart.

Timepoint [8] 371075 0
Timepoint 8: At the day of discharge
Secondary outcome [9] 371076 0
9. Readmissions - The cause of unplanned readmissions will be evaluated. We will check for readmissions up to 72 hours after discharge. We will collect the cause of readmission if this event happens
Timepoint [9] 371076 0
Timepoint 9: 72 hours after discharge
Secondary outcome [10] 371318 0
Vomiting episodes and severity using the Visual Analogue Scale (VAS) 0 – 100 (VAS; 0 = no vomiting, 100 = worst vomiting episode).
Timepoint [10] 371318 0
Timepoint 4: This will be measured every 30 minutes until the patient goes to the ward. Than VAS scores will be measured every 8 hours but not between 08:00p.m to 08:00a.m. The last measurement will be at 36h after T0.

Eligibility
Key inclusion criteria
Study population
Elective patients with osteoarthritis presenting for TKA at the Mackay Base Hospital.
Inclusion Criteria
ASA 1, 2 or 3
Age > 50 and < 85 years old
Capable to understand and consent for the research
Minimum age
50 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any contraindication to GA or NA
Chronic pain on opioids
Previous major surgery on the same knee
Inability to cooperate
Inability to have a reasonable English communication
Any contraindication for the medications we are using in this research
Rheumatoid arthritis

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)
Randomization and blinding procedure
Randomization will be performed by employees not involved in the clinical care of the patient. We will use an online tool (https://www.randomizer.org/). They will prepare an opaque-sealed envelopes containing the online generated allocation to either GA or SA. On the day of surgery an anaesthetic nurse, likewise not involved in the study, will open the envelope and will prepare the equipment accordingly. Subjects and investigating doctors will be blinded to treatment group until 1 h before surgery. After that, both subjects and personnel in the operation theatre will be, for obvious reasons, aware of the method of anaesthesia being prescribed. Postoperatively, staff responsible for monitoring and assessing home readiness will be blinded to treatment group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculations for this study were calculated using the R package ‘TrialSize’ (Zhang, E., Qian Wu, V., Chow, S.C., Zhan, H.G. (2015). TrialSize. R package version 1.3). The alpha was set at 0.01, the power at 0.9 and a 30% difference between GA and NA opioid levels was considered clinically significant. Based on this information, and considering that a medians test for differences in opioid use between the NA and GA groups would be the statistical test of main interest, a sample size of 24.78 (rounded up to 25) per group was calculated. This means a total sample size of 50 individuals. Further to this, a similar study by Kearns et al. (Kearns R. Anaesthesia. 2016 Dec;71(12):1431-1440. doi: 10.1111/anae.13620.) showed an approximate drop-out rate of 5% across groups in their study. As such, the current study proposes to recruit 27 participants (factoring in dropout rate) in each of the GA and NA groups in order to maximize our likelihood of finding a clinically significant difference of 30% in opioid use between our two groups using a comparison of medians test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2019
Actual
Date of last participant enrolment
Anticipated
1/12/2019
Actual
Date of last data collection
Anticipated
4/12/2019
Actual
Sample size
Target
54
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 13732 0
Mackay Base Hospital - Mackay
Recruitment postcode(s) [1] 26478 0
4740 - Mackay

Funding & Sponsors
Funding source category [1] 302755 0
Hospital
Name [1] 302755 0
Mackay Base Hospital
Country [1] 302755 0
Australia
Primary sponsor type
Individual
Name
Marcelo Epsztein Kanczuk
Address
Mackay Base Hospital
475 Bridge Rd, Mackay QLD 4740
Country
Australia
Secondary sponsor category [1] 302691 0
None
Name [1] 302691 0
Address [1] 302691 0
Country [1] 302691 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303357 0
Townsville Hospital and Health Service - Townsville Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 303357 0
Ethics committee country [1] 303357 0
Australia
Date submitted for ethics approval [1] 303357 0
27/05/2019
Approval date [1] 303357 0
Ethics approval number [1] 303357 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93386 0
Dr Marcelo Epsztein Kanczuk
Address 93386 0
Mackay Base Hospital
475 Bridge Rd, Mackay QLD 4740
Country 93386 0
Australia
Phone 93386 0
+61 0439392734
Fax 93386 0
Email 93386 0
[email protected]
Contact person for public queries
Name 93387 0
Marcelo Epsztein Kanczuk
Address 93387 0
Mackay Base Hospital
475 Bridge Rd, Mackay QLD 4740
Country 93387 0
Australia
Phone 93387 0
+61 0439392734
Fax 93387 0
Email 93387 0
[email protected]
Contact person for scientific queries
Name 93388 0
Marcelo Epsztein Kanczuk
Address 93388 0
Mackay Base Hospital
475 Bridge Rd, Mackay QLD 4740
Country 93388 0
Australia
Phone 93388 0
+61 0439392734
Fax 93388 0
Email 93388 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
individual participant data underlying published results only
When will data be available (start and end dates)?
Immediately following publication
End: 15 years after publication
Available to whom?
case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
any purpose. Case-by-case basis at the discretion of Primary Sponsor
How or where can data be obtained?
Data access will require to be approved by the Principal Investigator and it is a requirement to sign data access agreement.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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