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Trial registered on ANZCTR


Registration number
ACTRN12616001139460
Ethics application status
Approved
Date submitted
12/08/2016
Date registered
22/08/2016
Date last updated
10/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
To investigate the correlation between surgical pleth index and early postoperative pain/comfort in children aged 2 to 16 years of age who are undergoing surgery under general anaesthesia.
Scientific title
Correlation between Surgical Pleth Index and early postoperative comfort in children undergoing surgery under general anaesthesia.
Secondary ID [1] 289826 0
None
Universal Trial Number (UTN)
Trial acronym
CIPS (Comfort Index Post Surgery)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain experienced after surgery under general anaesthesia 299901 0
Condition category
Condition code
Anaesthesiology 299803 299803 0 0
Anaesthetics

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Observation of Surgical Pleth Index (SPI) and State Entropy (SE, validated depth of anaesthesia monitor) 5 minutes prior to emergence from anaesthesia. Recording of postoperative pain, measured 5-minutely on an age-appropriate 0-10 pain scale for 15 minutes after recovery room admission.

All patients will receive a routine general anaesthesia with sevoflurane based maintenance/with a laryngeal mask airway or an endotracheal tube at discretion of treating anaesthetist. All patients receive standard anaesthesia monitoring with addition of depth of anaesthesia monitoring with SE.
Clinical care will not deviate from routine practice (only children in whom an anaesthetic with sevoflurane/opioid +/- local/regional block is planned will be included, keeping MAC range between 0.8-1.3, see criteria below) for this study anaesthetic/analgesic drugs may be administered at any time during the study period (excluded medications, see below). If any of the excluded medications has to be administered, the patient will be withdrawn from the study protocol.

During the anticipated last 5 minutes of the surgery (last 5 minutes prior to anticipated lightening of depth of anaesthesia to state entropy more than 60, period of only mild surgical stimulation [i.e. skin closure, application of plaster or wound dressing]), data (blood pressure, heart rate, SE, SPI) are downloaded from the anaesthesia monitors (standard anaesthesia monitor at PMH plus portable anaesthesia monitor to collect data of SPI and SE) by means of a data collection software (S5 collect, GE Healthcare) and stored on a laptop PC. After the 5-minute period, it is anticipated that the attending anaesthetist will allow state entropy rated depth of anaesthesia to become lighter (= > 60) and that the patient will finally wake up from the anaesthetic. The latter may take place in the theatre or the recovery room). No influence will be made on the speed or method of patient arousal/extubation.

In the recovery room, as per routine clinical practice, a patient’s pain will be rated on a 0-10 pain scale every 5 minutes for 15 minutes (time counting from first time point a patient is deemed conscious and non-delirious. Pain will be assessed as usual at PMH via age-appropriate pain scales: Pain in the group 2-3 yrs. will be assessed using the FLACC (Face, Legs, Activity, Cry, and Consolability) score, in group 4-8 yrs. by the Revised Faces Pain Scale (FPS-R) and in group 9-16 yrs. by means of a Numeric Rating Scale (0 representing no pain and 10 the worst possible pain).

Treatment of pain will not be influenced by the protocol.
Intervention code [1] 295610 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299273 0
Definition of the optimum (highest combined sensitivity and specificity) cut-off value for Surgical Pleth Index (SPI) to distinguish between no to mild versus moderate to severe postoperative pain in children.
Pain will be measured using numerical rating scale (NRS; 0-10) for children aged 9-16, FPS-R for children aged 4-8 and FLACC for children aged 2-3.
Cut-off for pain scales are as follows:
No to mild = 0-4 and moderate to severe = 5-10 for NRS
No to mild = 0-4 and moderate to severe = 6-10 for FPS-R
No to mild = 0-4 and moderate to severe = 5-10 for FLACC
Timepoint [1] 299273 0
In the recovery room post operation, as per routine clinical practice, a patient’s pain will be rated on an age appropriate pain scale every 5 minutes for 15 minutes once the patient is deemed conscious and non-delirious.
Secondary outcome [1] 326703 0
Assessment of a potential variation in surgical pleth index in children depending on their age undergoing surgery under general anaesthesia. Participants are split between 3 age groups: 2-3 years, 4-8 years and 9-16 years
Timepoint [1] 326703 0
During the anticipated last 5 minutes of the surgery (last 5 minutes prior to anticipated lightening of depth of anaesthesia to state entropy > 60, period of only mild surgical stimulation [i.e. skin closure, application of plaster or wound dressing]), data (blood pressure, heart rate, SE, SPI).

Eligibility
Key inclusion criteria
Male or female patients, 2 to 16 years of age with an ASA of 1 2 or 3 who are scheduled for elective or urgent surgery under general anaesthesia (including laryngeal mask airway or endotracheal tube, state entropy monitoring) with sevoflurane.
Minimum age
2 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Lack of informed written consent and/or child assent (where appropriate), age less than 2 years or more than 16 years, poorly treated diabetes, moderate to severe intellectual disability, severe peripheral or cardiac neuropathy, pacemaker, treatment (infusion) with vasoactive medication, any pre or intraoperative treatment prior to the 5 minute observation period with ketamine, beta-receptor blockers, clonidine (as premedication, intraoperative use, or regional adjunct), beta-receptor agonists (i.e. Ventolin) or any other drug suspected to interact with the sympatho-vagal balance.
Muscle relaxant reversal using neostigmine, atropine or glycopyrrolate during the 15 minute observation period.
Propofol used during the 5 minute SPI observation period.
Surgery requiring a tourniquet (unless already deflated at start of intra-operative data acquisition interval).

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
105 patients will be enrolled over the 3 age groups (35 per group, grouped according to different pain scales used: 2 to 3 years, 4 to 8 years and 9 to 16 years.) as the sympatho-vagal balance in children is known to change with age. The proposal is essentially an accumulation of 3 pilot studies involving 30 patients in each project.
As the distribution of SPI values at the end of surgery in children is unknown, we aim to include data from the maximum number of patients per group (n=30) we can justifiably include in a pilot investigation. As in a previous study in adults 4 7 % of patients’ data could finally not be analysed due to technical problems, cancellations or protocol violations, and as we assume a slightly higher rate of such problems in children (based on previous experience at PMH), we ask to include 35 children per group in order to allow for a loss of up to approx. 15% of data.
While we can learn from the adult study with regards to the general study design and the timing of the measurements, we cannot use the adult data to extrapolate down to children since the sympatho-vagal balance is known to change with age.
A study population of n=30 per age group (90 in total) is a generally accepted number for pilot studies for monitoring devices for nociception to see if a clinically significant signal can be detected.
The Ledowski study (Ledowski T, Burke J, Hruby J. Surgical Pleth Index: prediction of postoperative pain and the influence of arousal. BJA 2016 in press) included data from 65 adult patients. Receiver-operating curve analysis showed as an optimum intra-operative cut-off SPI value of 30 to discriminate between NRS for pain (0-10) 0-3 vs. 6-10. For this value, the negative and positive predictive values (NPV/PPV) to discriminate between NRS scores 0-3 vs. 4-10 were 50% and 89.7%, respectively. SPI was significantly affected by arousal and SPI scores obtained during this phase were not predictive of postoperative pain.

Analysis of data will be made after checking all data for normal distribution (K-S test). Depending on the outcome, data found normally distributed will be displayed as mean (SD) vs. non-normally distributed data which will be displayed as median (25th/75th percentiles). For analysis of SPI, blood pressure and heart rate the mean or median (as appropriate) of the values collected over the 5 minute observation period will be used for further calculations. To investigate the correlation between SPI and pain scores, both the highest of the 3 pain scores as well as the mean/median will be used (using either Spearman’s or Pearson’s correlation coefficients, as appropriate). In order to dichotomize the recorded pain scores (both mean/median and highest of scores used), a rating of 0-3 will be used to reflect “no or mild” vs. scores from 4-10 “moderate-severe” pain. The calculation of receiver-operating characteristics (ROC) will allow us to investigate the sensitivity as well as specificity of different SPI scores for the prediction of moderate-severe pain. The SPI with the highest combined sensitivity and specificity will be used as cut-off value and for further analysis (positive and negative predictive value). Though principally any positive predictive value (PPV) of SPI for moderate-severe postoperative pain may be useful, we consider a PPV > 75% to be of clinical relevance.
For the definition of statistical significance, an alpha error of 5% and a beta error of 20% are set.

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)
WA
Recruitment hospital [1] 6482 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 14045 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 294300 0
Hospital
Name [1] 294300 0
Princess Margaret Hospital
Address [1] 294300 0
Princess Margaret Hospital
Roberts Road
Subiaco
WA 6008
Country [1] 294300 0
Australia
Funding source category [2] 294301 0
Hospital
Name [2] 294301 0
Royal Perth Children's Hospital
Address [2] 294301 0
Royal Perth Children's Hospital
Department of Anaesthesia and Pain Medicine
Wellington Street
Perth
WA 6000
Country [2] 294301 0
Australia
Primary sponsor type
Hospital
Name
Princess Margaret Hospital
Address
Roberts Road
Subiaco
WA 6008
Country
Australia
Secondary sponsor category [1] 293140 0
Individual
Name [1] 293140 0
Prof Britta Regli-von Ungern-Sternberg
Address [1] 293140 0
Department of Anaesthesia and Pain Management
Princess Margaret Hospital
Roberts Road
Subiaco
WA 6008
Country [1] 293140 0
Australia
Secondary sponsor category [2] 293141 0
Individual
Name [2] 293141 0
Prof Thomas Ledowski
Address [2] 293141 0
Royal Perth Hospital
Department of Anaesthesia and Pain Medicine
Wellington Street
Perth
WA 6000
Country [2] 293141 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295727 0
Princess Margaret Hospital for Children Ethics Committee
Ethics committee address [1] 295727 0
Level 1, Children's Clinical Research Facility
Princess Margaret Hospital
Roberts Road, Subiaco
Perth
WA 6008
Ethics committee country [1] 295727 0
Australia
Date submitted for ethics approval [1] 295727 0
01/06/2016
Approval date [1] 295727 0
10/08/2016
Ethics approval number [1] 295727 0
EP2016085

Summary
Brief summary
To date, validated depth of anaesthesia and depth of muscle relaxation monitors are available and routinely used in anaesthesia care. However, depth of analgesia has not been specifically monitored and anaesthetists tend to rely on clinical signs (i.e. blood pressure or heart rate) in order to estimate the need for intraoperative analgesics (i.e. opioids). However, the latter may be unreliable and hence a monitor for analgesia is highly desirable. Surgical Pleth Index (SPI) is a score (0-100), which is calculated from the beat-to-beat interval of the heart rate and also the peripheral pulse wave amplitude. Essentially, this data is utilized to reflect the cardiac and peripheral sympathetic tone of a patient – the latter is assumed to correlate with the depth of analgesia. The acquisition of this raw data is achieved via the standard peripheral oxygen saturation sensor and the latter is then computed into the normalized score. SPI requires no change of anaesthesia technique nor any extra monitors or consumables. It’s merely a software patch for GE monitoring systems. Though SPI has been demonstrated to reflect intraoperative stimuli (i.e. knife to skin incision), it cannot be used in awake patients as then the score is subjected to too many artefacts (e.g., arousal is a strong sympathetic stimulant). However, a recent study by Ledowski et al. at Royal Perth Hospital, Perth, Australia has shown a high positive predictive value for SPI more than 30 monitored just before patient arousal to indicate moderate-severe postoperative pain. Though this is promising, no study has yet investigated this matter in children. This observational trial proposes to prospectively investigate the association of SPI with postoperative pain in the recovery room in children from 2 to 16 years.

Hypothesis: SPI during the last minutes of surgery may be predictive of moderate-severe acute postoperative pain on recovery room admission.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67954 0
Prof Britta Regli-von Ungern-Sternberg
Address 67954 0
Department of Anaesthesia and Pain Management,
Princess Margaret Hospital for Children,
Roberts Road,
Subiaco,
WA 6008
Country 67954 0
Australia
Phone 67954 0
+61893408109
Fax 67954 0
Email 67954 0
Britta.Regli-VonUngern@health.wa.gov.au
Contact person for public queries
Name 67955 0
Prof Britta Regli-von Ungern-Sternberg
Address 67955 0
Department of Anaesthesia and Pain Management,
Princess Margaret Hospital for Children,
Roberts Road,
Subiaco,
WA 6008
Country 67955 0
Australia
Phone 67955 0
+61893408109
Fax 67955 0
Email 67955 0
Britta.Regli-VonUngern@health.wa.gov.au
Contact person for scientific queries
Name 67956 0
Prof Britta Regli-von Ungern-Sternberg
Address 67956 0
Department of Anaesthesia and Pain Management,
Princess Margaret Hospital for Children,
Roberts Road,
Subiaco,
WA 6008
Country 67956 0
Australia
Phone 67956 0
+61893408109
Fax 67956 0
Email 67956 0
Britta.Regli-VonUngern@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary