Summary

Rationale

Monitors that use the electroencephalogram (EEG) to assess anesthetic depth in patients undergoing surgery are now widely available. General anesthesia that is performed without depth of anesthesia monitoring, tends to be relatively deep to ensure a lack of awareness. Five of six recent observational studies have shown a 20% increase in mortality in moderate or high risk patients undergoing major surgery who receive relatively deep anesthesia  but this needs to be balanced against a possible increase in the risk of awareness if patients are given lower doses of anesthetic drugs. The optimal depth at which anesthetics should be administered is unknown.

Aims

We plan to perform a large scale randomised trial of ‘deep’ versus ‘light’ anesthesia to definitively answer the question of whether anesthetic depth alters perioperative outcome. The primary outcome variable will be all-cause mortality at one year and secondary outcomes will include differences in other complications of surgery and anesthesia  including wound infection, cardiovascular complications, stroke, continuing pain and occurrence of awareness.

Design and Methods

This will be a prospective, randomized, double blind (subjects, investigators, outcomes assessors), active control, parallel assessment, intention to treat, safety and efficacy study. Patients will be monitored with the bispectral index (BIS). Patients will be randomised to BIS targets of either 50 or 35. Inclusion criteria are: age ≥60 years, moderate or high risk (ASA grade 3 or 4), surgery lasting ≥2 hours, all general anaesthesia including with major regional block.

Exclusion criteria

Unable to monitor BIS, not expected to survive one year, unable to consent, not expected to be contactable in one years time, surgery with a wake-up test.

The primary outcome is survival at one year after surgery. One year mortality in this group of patients is expected to be 10%. A 20% reduction in survival with light anesthesia requires a total of 6500 patients (588 events), =0.8, =0.049. This is based on the assumption that the accrual period will be 3 years and the follow up period will be 1 year. A composite score of post-operative complications including myocardial infarction, stroke, sepsis, renal failure, pneumonia and wound infection will also be assessed. These complications will also be analysed using Cox’s proportional hazards modelling to develop univariate predictors of mortality. Cancer recurrence and the incidence of awareness under anesthesia will also be recorded. An independent Data Safety and Monitoring Board will oversee the study.

Research Impact

The study aims to test the ability of a widely available monitoring technology (BIS) to improve outcomes in a wide range of diseases for which major surgery is the chosen treatment. Over 450,000 people in New Zealand and 234 million people worldwide undergo surgery each year for both acute and chronic conditions. About 10% of these people are in higher risk categories and having extensive surgery that is the target group for this study. A positive study would have important implications for public health and its costs, with the anticipated improvement in one-year survival being 20% in older patients undergoing major surgery or a 2% absolute risk reduction. A negative study would also have important implications for how we administer anesthesia in the sick and elderly patient. The findings are eminently translatable into clinical practice because most hospitals already have these anesthetic depth monitors available. The result will suggest best practice in an area where there is currently no guidance.

Trial Summary

Study Size6500 patients
Study DesignInternational multicentre double blind, prospective, intention to treat, safety & efficacy study
Primary OutcomeOne year mortality
Secondary Outcomes
  • Myocardial Infarction
  • Cardiac Arrest
  • Pulmonary Embolism
  • Stroke
  • Sepsis
  • Surgical Site Infection
  • ICU stay
  • Hospital stay
  • Awareness
  • WHODAS Score
  • Persistent Postoperative Pain
  • Cancer Recurrence

Study Protocol

Study Size 6500 patients
Study Design International multicentre double blind, prospective, intention to treat, safety & efficacy study
Primary Outcome One year mortality
Secondary Outcomes Incidence of MI, stroke, pneumonia, wound infection, pulmonary embolism, ICU stay, hospital stay, cancer recurrence
Inclusion Criteria ≥60 years, ASA status 3 or 4, surgery lasting >2 hours, post-op hospital stay 2+ nights, general anaesthesia with or without major regional block, able to monitor BIS
Study Protocol
Pre-operative  Age, weight, height, ASA status, ECGCharlson co-morbidity score
Randomisation Stratification by centre, 1:1 randomisation to BIS 35 or BIS 50 groups. On-line, Iphone App and telephone randomization available.
 Intra-operative  Pre-defined blood pressure targetRandomised BIS target of 35 or 50Computerised recording of BIS, BP, HR and ETvolatile conc.

Cancer status (tumour-node-metastasis score)

Post-operative day 1-3 Katz quality of recovery scoreBrice awareness questionnaire (day 1 only)Adverse outcomes: MI, stroke, pneumonia, wound infection, pulmonary embolism, ICU admission

Analgesic and antiemetic requirements

Post-operative day 30 SurvivalAdverse outcomes: MI, stroke, pneumonia, wound infection, pulmonary embolismICU stay, hospital stay

Ongoing analgesic or antiemetic requirement

Cancer staging

    1 year follow-up SurvivalAdverse outcomes: MI, stroke, pneumonia, wound infection, pulmonary embolismCancer recurrence

Persistent post-operative pain

 

Secondary outcomes

  • Myocardial Infarction
  • Cardiac Arrest
  • Pulmonary Embolism
  • Stroke
  • Sepsis
  • Surgical Site Infection
  • ICU stay
  • Hospital stay
  • Awareness
  • WHODAS Score
  • Persistent Postoperative Pain
  • Cancer Recurrence

Funding

New Zealand

  • Health Research Council Project Grant 12‐308‐Short

Australia

  • NHMRC Project Grant APP1042727

Hong Kong

  • RGC Project Grant