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Trial registered on ANZCTR


Registration number
ACTRN12615000789561
Ethics application status
Not yet submitted
Date submitted
16/03/2015
Date registered
30/07/2015
Date last updated
30/07/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized and controlled study comparing efficacy of intra-operative patient controlled sedation versus radiologist controlled sedation using midazolam and fentanyl, for patients undergoing insertion of a central venous line.
Scientific title
A randomized and controlled study comparing efficacy of intra-operative patient controlled sedation versus radiologist controlled sedation using midazolam and fentanyl, for patients undergoing insertion of a central venous line.
Secondary ID [1] 286368 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Radiologically-guided insertion of a central venous line for patients undergoing chemotherapy, dialysis, or other conditions requiring high flow long term central line access (eg treatment of cystic fibrosis or other chronic disease) 294506 0
Condition category
Condition code
Anaesthesiology 294811 294811 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Having previously completed a pilot study on this topic (see previous submission ID number ACTRN12614001280695), we are progressing to a randomised controlled trial comparing the effectiveness of intra-operative patient–controlled sedation against radiologist controlled sedation with midazolam and fentanyl for patients undergoing insertion of a central venous line.

This practice will allow the patient to self-administer a controlled dose of sedation/analgesia which then has a lock-out period. This will be done using a standard hospital patient controlled analgesia (PCA) pump which are in wide use in postoperative patients.

The intervention will allow patient's access to the PCA device from the beginning of the procedure (after 'time out' has been done) until the procedure finishes and the drapes are removed. Each button press will deliver a dose of 1 mg midazolam and 25 micrograms fentanyl. This will have a 3 minute lockout interval and there will be a maximum of 8 button presses (based on the size of the syringe) . Patient's will be instructed as to the way to use the device.

This practice will help to allow better control of sedation and potentially reduce the risk of underdosing and overdosing while providing patients an overall satisfactory sedation experience.

The radiologist will prescribe the medication. The medication and device will be controlled by one of 2 radiology nurses who will be monitoring the vital signs of the patient during the procedure.
Intervention code [1] 291429 0
Treatment: Drugs
Intervention code [2] 291430 0
Treatment: Devices
Comparator / control treatment
The control group will consist of the the current gold standard, which is radiologist controlled sedation.

After assessment of the patient, their relevant history, and brief examination an assessment is made as to the level of sedation required for that patient. The radiologist will prescribe sedation as he/she feels is required during the procedure. This will usually be in aliquots of 1mg midazolam and 50 micrograms fentanyl. There is however no specific guidelines as to how much and when it is best to give this sedation. This is the current standard of care.

The medical procedure that will be performed on the patient and the indications for the procedure will be the same between the control and intervention group.
Control group
Active

Outcomes
Primary outcome [1] 294570 0
Patient satisfaction with procedure measured with the 10 point VAS Patient Satisfaction Survey
Timepoint [1] 294570 0
Measured at 2 hours post the procedure
Primary outcome [2] 294571 0
Patient duration of amnesia for specified stimuli during the procedure, measured by questioning patients about the stimuli 1 hour after the procedure. This is a questionnaire that has been specifically designed for the study.
Timepoint [2] 294571 0
1 hour after the procedure
Primary outcome [3] 294572 0
Success of sedation and analgesia measured by the Victorian Standard Sedation Score
Timepoint [3] 294572 0
Measured at selected time points during the procedure and immediately after the procedure:
Time 1 - Pre-procedure
Time 2 - After time out the procedure begins and the PCA is active
Time 3 - Prep and drape
Time 4 - Local anaesthetic
Time 5 - During the 'tunneling' process of the ventral line procedure
Time 6 - End of procedure - drapes removed, PCA removed
Secondary outcome [1] 313613 0
Safety assessed by the composite number of procedural, pre-discharge and 24 hour adverse events measured by Common Terminology Criteria for Adverse Events v4
Possible adverse effects include:
1 - undersedation (this is common but less likely to occur with this patient-controlled technique)
2 - overdosing (also unlikely to occur as patient will be sedation and unable to activate PCA button)
3 - paradoxical effects of sedation - transient disinhibition sometimes seen during light sedation
4 - hypotension - uncommon response to midzazolam and usually asymptomatic given the patient will be supine for the procedure
Timepoint [1] 313613 0
Recorded at discharge (2 hrs after procedure)
Secondary outcome [2] 313614 0
Level of intra-operative pain measured every 10 minutes and level of pain at the end of the procedure measured with the Victorian Acute Pain Management Measurement Toolkit
Timepoint [2] 313614 0
Every 10 minutes during procedure and once after the procedure
Secondary outcome [3] 313615 0
Suitability for discharge at 2 hours post procedure, measured by the Modified Post Anaesthesia Discharge Scoring System (MPADSS)
Timepoint [3] 313615 0
2 hours post procedure
Secondary outcome [4] 313616 0
Numbers and timing of button requests from the PCA unit that are not successful, ie during the administration of a prior successful request: these unsuccessful requests are a measure of patient demand for sedation and therefore underdosing
Timepoint [4] 313616 0
From the start of the procedure to removal of drapes
Secondary outcome [5] 313617 0
Cumulative dose of midazolam and fentanyl measured by reference to the PCA system
Timepoint [5] 313617 0
From the start of the procedure to removal of drapes

Eligibility
Key inclusion criteria
Patients referred to the Radiology Department for elective central venous line insertion (for example, but not limited to: Hickman line for chemotherapy or antibiotics, Portacath for commencement urgent dailysis)
Males and females aged 18 to 75
No allergy to fentanyl and/or midazolam
ASA score 1 to 3
Signed study participant information and Consent form.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pregnancy
Coagulopathy (INR > 2, platelets < 50)
Abnormal renal function with a calculated e-GFR <40;
Allergy to contrast;
ASA score 4 to 6
Therapeutic heparinisation or current thrombolysis
Sepsis
Cellulitis or dermatitis at planned insertion site
On protease inhibitor antiretroviral drugs
Altered conscious state
Head injury
Significant hepatic dysfunction
Head or neck tumours
Not fasted for at least 4 hours
Contraindication to administration of inspired oxygen
Unable to sign participant information and Consent form
Lacks capacity to provide study consent for self

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 Alfred patient ‘opt-out of research register’ will be checked by the Radiology Research Unit.
In-patients and patients from Alfred out-patient clinics are referred to the Radiology Department for CVA line insertion and bookings are made 48 hrs to one month in advance of the procedure date. When a referral is obtained potential participants will be seen by the rostered interventional radiologist/fellow on the ward or admission clinic and told about the study. If they are interested in participating they will be given a participant information and consent form, some time to study it, and then some opportunity to ask questions of the investigators. Potential participants will be asked about their understanding of the study. Study participant consent will be obtained by the study coordinator or procedural radiologist. Procedural consent will be obtained by the radiologist.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computerised randomisation program will be used. The randomised data will be placed in an envelope and opened at the time of performing the procedure.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Studies comparing PCA to IR administered sedation and analgesia are limited. Sample size calculations were based on data in the literature comparing PCA to anaesthetist managed sedation for ECRP. With 20 patients per group this study should have an 80% power to detect a difference in a continuously normally distributed outcome equivalent to 1/2 standard deviation with a two-sided p-value of 0.05.

Data analysis will involve confirmation of data characteristic followed by appropriate testing. Parametric data will be analysed with student t-testing, while non-parametric variables will be analysed using Wilcoxon Rank Sum testing. Binomial data will be analysed using Chi Squared of Fisher’s Exact testing as appropriate. P <0.05 will be considered significant.

Sample size estimates were confirmed with data from a 10 patient pilot study and an age, gender and indication matched control group (routine patients having CVC insertion with routine RCS) and also confirmed by the AMREP biostatistician. The dose of administered fentanyl had the highest variation and was used for the sample size calculation. From our pilot data, the mean (SD) dose of fentanyl in the control and PCS groups was found to be 70 (28) and 150 (46) respectively. We calculated that a sample of 10 patients per group would provide a statistical power of 90% with a two-tailed significance level of 0.05 to detect a difference of 70 mg between groups using a standard deviation of 46 mg. This number has been further increased to 20 patients per group as it is feasible within the time available and judged to be adequate to give reasonable numbers for analysis.

Analyses will be performed after the first 40 patients to determine if the other endpoints are adequately powered.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/08/2015
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 3567 0
The Alfred - Prahran
Recruitment postcode(s) [1] 9378 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 290937 0
Self funded/Unfunded
Name [1] 290937 0
N/A
Country [1] 290937 0
Primary sponsor type
Hospital
Name
Alfred Hospital
Address
Commercial Road,
Prahran 3181
Victoria
Country
Australia
Secondary sponsor category [1] 289622 0
None
Name [1] 289622 0
N/A
Address [1] 289622 0
N/A
Country [1] 289622 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 292541 0
Alfred hospital ethics committee
Ethics committee address [1] 292541 0
Commercial Road,
Prahran 3181
Victoria
Ethics committee country [1] 292541 0
Australia
Date submitted for ethics approval [1] 292541 0
23/03/2015
Approval date [1] 292541 0
Ethics approval number [1] 292541 0

Summary
Brief summary
Diagnostic and therapeutic procedures performed in interventional radiology can provoke anxiety and may be painful. Mild sedation with analgesia is administered by the interventional radiologist to calm patient anxiety, reduce unwanted movements and alleviate patient discomfort.

Central line placements are common, (including Hickman line placement, tunnelled dialysis catheter placement, injectable port implantation) and intravenous sedation would typically be used for these procedures.

The most commonly used drug for sedation in radiology is midazolam, a benzodiazepine. Midazolam has a short half-life of 2-6 hrs, but very powerful anxiolytic (anti-anxiety), amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative actions. It is administered at 1 milligram per dose to the desired response, has a 2 minute onset time and duration of 45 to 60 minutes.

The most common analgesic used is fentanyl, a short acting opioid that is administered at an incremental dose of 25 micrograms and repeated every 5 minutes to a maximum dose of 100 micrograms. Its onset time is 2-3 minutes and it has a duration time of 30-60 minutes.

Midazolam and fentanyl are usually administered concurrently, with 1 milligram midazolam and 25 micrograms fentanyl being the standard single dose. Multiple doses are titrated carefully to achieve and maintain adequate sedation and alleviation of anxiety, while preserving cardio-respiratory function, protective reflexes and the ability to respond appropriately to verbal and/or tactile stimulation. Doses are given incrementally, often starting with a double dose with at least 5 minutes interval before the next dose to allow evaluation of drug effect. Oxygen saturation, blood pressure, heart rate, and respiratory rate are monitored continuously and documented every 10 minutes. Neurological response is also monitored continuously by observing the patients response to command or conversation. Reversal "antidote" agents for these medications are flumazenil and naloxone respectively.

The current practice is that the radiologist takes a history from the patient, looking for patient factors that may affect the safety and practice of sedation. These would include patient size, age, prior cardiac and respiratory disease, diabetes, renal failure, obesity, allergies, drug interactions, previous anaesthetic history, and airway issues. There will be assessment of the patient’s level of anxiety and expectation of procedural discomfort. The radiologist will then decide on the appropriateness of midazolam/fentanyl sedation, and choose an initial dose. As the procedure starts, the level of sedation is assessed, and if needed, further aliquots of midazolam/fentanyl are administered at the radiologists’ discretion.

Our hypothesis is that this practice has problems in that there is a fear of the effects of oversedation (eg low blood pressure or slower respiratory rate), and this results in many patients being undersedated. The patient may be apprehensive to ask for more sedation and thus their overall experience of the procedure is suboptimal. Based on prior evidence in the literature in other medical settings, we believe that by giving the control of sedation to the patient (within a safe dose and lockout period), that the patient is more likely to seek sedation when required and hence will be at less risk of undersedation. We expect that this will lead to an overall greater experience for the patient. The medical procedure being performed (ie insertion of a tunnelled central line) will not be affected by this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55838 0
Dr Tom Snow
Address 55838 0
Alfred Hospital Department of Radiology Commercial Road Prahran 3181 Victoria
Country 55838 0
Australia
Phone 55838 0
+61390762118
Fax 55838 0
Email 55838 0
[email protected]
Contact person for public queries
Name 55839 0
Helen Kavnoudias
Address 55839 0
Alfred Hospital Department of Radiology Commercial Road Prahran 3181 Victoria
Country 55839 0
Australia
Phone 55839 0
+61390762118
Fax 55839 0
Email 55839 0
[email protected]
Contact person for scientific queries
Name 55840 0
Helen Kavnoudias
Address 55840 0
Alfred Hospital Department of Radiology Commercial Road Prahran 3181 Victoria
Country 55840 0
Australia
Phone 55840 0
+61390762118
Fax 55840 0
Email 55840 0
[email protected]

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