Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000825752
Ethics application status
Approved
Date submitted
21/07/2013
Date registered
26/07/2013
Date last updated
31/01/2019
Date data sharing statement initially provided
31/01/2019
Date results information initially provided
31/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Pilot Study on the Clinical Significance of Cerebrovascular Autoregulation Monitoring during Non-Cardiac Anaesthesia
Scientific title
In elderly, unwell patients presenting for major non-cardiac surgery, does the Tissue Oxygenation Index predict cerebral ischaemia episodes associated with worse clinical outcomes.
Secondary ID [1] 282875 0
Nil
Universal Trial Number (UTN)
U1111-1145-8724
Trial acronym
BALANCED-TOx
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-operative recovery, mortality, and morbidity from major surgery 289693 0
cerebrovascular autoregulation
 289694 0
Condition category
Condition code
Anaesthesiology 290013 290013 0 0
Anaesthetics

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
In this observational study, near infrared spectroscopy will be used to measure cerebral tissue oxygenation saturation during major surgery, as a surrogate measure of cerebral blood flow. A moving Pearson correlation index between cerebral saturation and mean arterial pressure is derived to produce the Tissue Oxygenation (TOx) Index, lower limit of cerebrovascular autoregulation (LLA), and the optimal blood pressure of unimpaired autoregulation (ABPopt). TOx, ABPopt, and LLA data is collected non-invasively during anaesthesia in an elderly population presenting for major non-cardiac surgery. These will be analysed against patient outcomes of post-operative recovery, mortality, and morbidity to assess strength of association, and predictive ability of post-operative risk stratification. The trial duration is expected to be 1 year.
Intervention code [1] 287577 0
Not applicable
Comparator / control treatment
standard treatment: general anaesthesia with volatile anaesthetic only, bispectral index monitoring, arterial line monitoring. No restriction on anaesthesia medications except for no nitrous oxide, and ketamine infusions <25mg/hr. No restriction on opioids. Regional anaesthesia and local anaesthesia may be provided at discretion of anaesthetic team or surgical team.
Control group
Active

Outcomes
Primary outcome [1] 290059 0
Incidence of recovery of the cognitive domain at Day 3, as measured using the Post-Operative Quality of Recovery Score
Timepoint [1] 290059 0
Day 3 post-operative
Secondary outcome [1] 303850 0
All cause mortality - via medical records or autopsy report
Timepoint [1] 303850 0
Day 30
Secondary outcome [2] 303851 0
End organ morbidity:
1 Myocardial infarction, defined as a typical rise of cardiac troponin, or typical fall of an elevated troponin, or a rapid rise and fall of CK-MB, plus one of the following: ischaemic symptoms, changes in electrocardiography indicative of ischaemia, pathological Q waves, wall motion changes in echocardiography or nuclear medicine scan, coronary angiography, or autopsy results confirming myocardial infarction

2 Cardiac arrest, defined as a successful resuscitation from either documented or presumed ventricular fibrillation or sustained ventricular tachycardia or asystole

3 Pulmonary embolism, defined as a high probability ventilation-perfusion scan, spiral computerised tomography (CT) scan, pulmonary angiography, or at autopsy

4 Stroke, defined as a cerebral infarction or haemorrhage on a CT or magnetic resonance imaging (MRI) scan, with new neurological symptoms (paralysis, weakness, or speech difficulties) associated with the area of stroke, lasting longer than 24 hours or resulting in death

5 Sepsis, defined as positive blood cultures or purulent discharge from any site, with criteria of systemic inflammatory response syndrome

6 Surgical site infection, defined if purulent discharge associated with/or positive microbial culture

7 Acute kidney injury, defined as meeting criteria for at least RIFLE Class I, with greater than or equal to 2 fold increase in serum creatinine from pre-operative baseline, or estimated glomerular filtration rate decrease of greater than or equal to 50% from baseline, or urine output less than or equal to 0.5ml/kg/hr for 12 hours
Timepoint [2] 303851 0
Day 30
Secondary outcome [3] 303852 0
Length of hospital stay, as determined by interrogating medical record (in days)
Timepoint [3] 303852 0
number of days of hospital admission, recorded at end of hospital admission
Secondary outcome [4] 303853 0
Unplanned admission to Intensive Care Unit, as noted in the medical and anaesthetic record
Timepoint [4] 303853 0
At any time during admission, monitored daily
Secondary outcome [5] 303854 0
Disability free survival, defined as survival and freedom from new-onset disability as measured by a 4-point reduction from the baseline pre-operative WHODAS-12 score
Timepoint [5] 303854 0
Baseline measured before operation, versus Day 30 post operatively

Eligibility
Key inclusion criteria
Adult patients presenting for non-cardiac surgery, who fulfil the following:
* age greater than or equal to 60 years old
* American Society of Anesthesiologists (ASA) physical status 3 or 4
* elective major surgery, defined as operations expected to last greater than or equal to 2hours, and post-operative hospital stay of greater than or equal to 2 nights
* General anaesthesia with or without major regional anaesthesia
* have standard anaesthetic management, which includes the following monitoring: arterial catheter pressure waveform, end-tidal volatile agent concentrations, and non-invasive processed electroencephalography (Bispectral index, BIS)
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Certain non-cardiac surgical operations, due to the surgical site either adjacent or interfering with the near infrared spectroscopy optode placement, or of the recording electrodes of the depth of anaesthesia monitor, will be ineligible for recruitment. These are intracranial and extracranial neurosurgical and head/neck operations
* unable to consent
* surgery with "wake-up" testing
* Patients who are not fluent in English, as they may be unable to complete questionnaires designed for Post-operative Quality of Recovery testing relevant to post-operative recovery
* Patients, who at the discretion of the treating anaesthetist, receives a total intravenous general anaesthetic (TIVA) technique instead of an inhalational general anaesthesia
* previous enrolment in the BALANCED depth of anaesthesia and patient outcomes study

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Cognitive recovery in PQRS, and new onset disability as measured by WHODAS-2 will be treated as binary outcomes. Chi squared test of association will be used for these outcomes versus impaired cerebral autoregulation. Logistic regression will be used to determine the strength of relationship between all measured NIRS derived values (specifically, rSO2, HbI, TOx, LLA, ABPopt, and min x mmHg and min x % measures of duration-severity of ischemia) and new onset disability. Threshold values of the TOx will be analysed to determine best association with the primary outcome, at >0.3, >0.35, and >0.4 values. Logistic regression will also be used to determine the relationship between each of the binary end organ morbidity and mortality outcomes, unplanned ICU admission, length of hospital stay, and secondary quality of recovery outcomes from PQRS and QoR-15, to NIRS derived values.
All analyses will additionally examine the effect of adjusting for important co-variates, such as age, body mass index, ASA status, and Charlson co-morbidity score. Relationships for which the p value is <0.05 will be deemed significant

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/04/2014
Actual
1/06/2014
Date of last participant enrolment
Anticipated
Actual
1/01/2017
Date of last data collection
Anticipated
Actual
1/02/2017
Sample size
Target
150
Accrual to date
Final
142
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 1351 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 7186 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 287660 0
Self funded/Unfunded
Name [1] 287660 0
Country [1] 287660 0
Primary sponsor type
Hospital
Name
Liverpool Hospital, South West Sydney Local Health District
Address
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170
Country
Australia
Secondary sponsor category [1] 286398 0
None
Name [1] 286398 0
Address [1] 286398 0
Country [1] 286398 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289623 0
South West Sydney Local Health District HREC
Ethics committee address [1] 289623 0
Research and Ethics Office
Level 2, UNSW Clinical School
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170
Ethics committee country [1] 289623 0
Australia
Date submitted for ethics approval [1] 289623 0
05/08/2013
Approval date [1] 289623 0
18/11/2013
Ethics approval number [1] 289623 0

Summary
Brief summary
This study is a prospective, single centre, observational pilot study examining the clinical relevance and outcomes of changes in cerebral vascular autoregulation during general anaesthesia in patients presenting for non-cardiac surgery. Primary outcome is post-operative quality of recovery, and secondary outcomes are patient mortality and major morbidity.
This study is a sub-study of a larger, multicenter study on the effect of depth of anaesthesia on patient outcomes (BALANCED study).

Recent animal and human studies have investigated indices of cerebrovascular autoregulation (CVAR), including the tissue oxygenation index (TOx), cerebral oximetry index, haemoglobin volume index, and pressure reactivity index. These indices are derived from measuring different surrogates of cerebral blood volume or cerebral blood flow, and calculating a moving correlation coefficient between the surrogate and mean arterial pressure.

Specifically, the TOx index measures cerebral tissue oxygenation using non-invasive near infrared spectroscopy (NIRS) as a surrogate of cerebral blood flow and correlation with mean arterial pressure (MAP). Thus, a TOx index can reflect CVAR changes in blood vessel diameter to maintain a constant cerebral blood flow despite changes in systemic arterial blood pressure. The TOx index is thus a novel measure of adequacy of cerebral perfusion.

We hypothesise that patients who have impairment in CVAR may be exposed to episodes of cerebral ischaemia resulting in end organ dysfunction. In a number of prospective observational studies recruiting cardiac surgical patients undergoing cardiopulmonary bypass, impaired autoregulation has been associated with cerebral injury, stroke and acute kidney injury. These studies have also defined a threshold level of MAP when autoregulation is lost, as well as a range of MAP when autoregulation is optimised.

However, our understanding of this association is incomplete. This study will improve this understanding in a non-cardiac surgical population who are at higher risk of complications after anaesthesia. Elderly patients greater than or equal to 60 years old admitted for major non-cardiac surgery will be monitored using NIRS to derive a real-time TOx index. We will prospectively measure patient outcomes including post-operative quality of recovery, symptoms and signs of major organ dysfunction, and mortality. Statistical analysis will be performed to determine the strength of association between patient outcomes and episodes of cerebral ischaemia as detected by TOx.

This study will also provide essential data to help design a future randomised clinical trial. We would plan an interventional arm using the TOx index and the optimal autoregulation MAP value, as goal-directed therapy to minimise the time that patients are exposed to potential cerebral ischaemia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 41618 0
Dr Alwin Chuan
Address 41618 0
Department of Anaesthesia
Room 124
Level 1
New Clinical Building
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170
Country 41618 0
Australia
Phone 41618 0
+61 407743668
Fax 41618 0
Email 41618 0
dr.chuan@iinet.net.au
Contact person for public queries
Name 41619 0
Alwin Chuan
Address 41619 0
Department of Anaesthesia
Room 124
Level 1
New Clinical Building
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170
Country 41619 0
Australia
Phone 41619 0
+61 407743668
Fax 41619 0
Email 41619 0
dr.chuan@iinet.net.au
Contact person for scientific queries
Name 41620 0
Alwin Chuan
Address 41620 0
Department of Anaesthesia
Room 124
Level 1
New Clinical Building
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170
Country 41620 0
Australia
Phone 41620 0
+61 407743668
Fax 41620 0
Email 41620 0
dr.chuan@iinet.net.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
no ethics clearance for IPD


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Chuan A, Short TG, Peng AZY, Wen SYB, Sun AX, Ting... [More Details]

Documents added automatically
No additional documents have been identified.