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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 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]

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

cerebrovascular autoregulation

Condition category

Condition code

Anaesthesiology

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]

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]

Incidence of recovery of the cognitive domain at Day 3, as measured using the Post-Operative Quality of Recovery Score

Timepoint [1]

Day 3 post-operative

Secondary outcome [1]

All cause mortality - via medical records or autopsy report

Timepoint [1]

Day 30

Secondary outcome [2]

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]

Day 30

Secondary outcome [3]

Length of hospital stay, as determined by interrogating medical record (in days)

Timepoint [3]

number of days of hospital admission, recorded at end of hospital admission

Secondary outcome [4]

Unplanned admission to Intensive Care Unit, as noted in the medical and anaesthetic record

Timepoint [4]

At any time during admission, monitored daily

Secondary outcome [5]

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]

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?

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]

Liverpool Hospital - Liverpool

Recruitment postcode(s) [1]

2170 - Liverpool

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

South West Sydney Local Health District HREC

Ethics committee address [1]

Research and Ethics Office
Level 2, UNSW Clinical School
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

05/08/2013

Approval date [1]

18/11/2013

Ethics approval number [1]

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

Dr Alwin Chuan

Address

Department of Anaesthesia
Room 124
Level 1
New Clinical Building
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170

Country

Australia

Phone

+61 407743668

Fax

dr.chuan@iinet.net.au

Contact person for public queries

Name

Alwin Chuan

Address

Department of Anaesthesia
Room 124
Level 1
New Clinical Building
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170

Country

Australia

Phone

+61 407743668

Fax

dr.chuan@iinet.net.au

Contact person for scientific queries

Name

Alwin Chuan

Address

Department of Anaesthesia
Room 124
Level 1
New Clinical Building
Liverpool Hospital
Elizabeth Street
Liverpool NSW 2170

Country

Australia

Phone

+61 407743668

Fax

dr.chuan@iinet.net.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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