Anaesthetic depth and complications after major surgery: an international, randomised controlled trial

Short TG, Campbell D, Frampton C et al.

The Lancet 2019 394: 1907-1914. https://doi.org/10.1016/S0140-6736(19)32315-3

Aims of Study

To identify any difference in all-cause one-year mortality in patients over 60 having major surgery, between those assigned to either light or deep general anaesthesia as measured by bispectal [BIS] index.

Design and Location

An international, randomised, patient and assessor blinded trial conducted in seven countries with 73 centres taking part. Both the principal investigator site and the independent monitoring committee were based in New Zealand.

Methodology

Inclusion Criteria:

• 60 years or older having surgery with an expected duration of more than 2 hours
• American Society of Anaesthesiologists (ASA) Physical Status Classification: 3 or 4
• Anticipated Hospital stay post operatively of over 2 days

Exclusion Criteria:

• Inability to place or monitor BIS index (due to site or surgery, planned ‘wake up’ test)
• Use of Nitrous Oxide or Propofol for maintenance of anaesthesia and the use of ketamine at infusion rates of more than 25mg/hour
• Expected to be uncontactable at one year follow up

Method

• Anaesthetists performing the procedure were asked to choose a MAP target range appropriate for before learning group allocation
• BIS targets of 50 and 35 were chosen as the aim for general anaesthesia. These were chosen from previously published research of similar patients, with these numbers the first and third quartiles of the mean BIS obtained during these operations.
• After induction, anaesthetists were required to maintain either a ‘light’ (BIS 50) or ‘deep’ (BIS 35) anaesthesia using volatile anaesthetic agents. They were required to maintain within 5 units of the target BIS and also maintain MAP within their chosen target range
• Anaesthetists were not expected to maintain the BIS target to an extent that could compromise patient safety.
• All drugs given, the minimum alveolar concentration (MAC), mean arterial blood pressure (MAP) were recorded and a mean value of each was calculated for each surgery.
• Patients were followed up on the post anaesthesia care unit on days 1 to 3 following surgery, at hospital discharge and at 30 days and 1 year
• A 15 item ‘quality of recovery score’ was used on days 1,2,3 and 30 postoperatively and the WHODAS 2.0 score was used at days 30 and 1 year to determine disability/morbidity

Primary Outcome

• All cause one-year mortality

Secondary Outcome

• Incidence of myocardial infarction, cardiac arrest, pulmonary embolism or stroke
• Incidence of sepsis or surgical site infection
• Total intensive care unit stay
• Incidence of awareness during anaesthesia
• WHODAS 2.0 score at 30 days and 1 year and ‘disability free survival’ (defined as alive and less than 4-point reduction in WHODAS Score 2.0 at one year)
• Persistent Pain
• Cancer recurrence

Statistics

An intention to treat analysis was initially used to analyse the primary and secondary outcomes. With an expected one-year survival of 90%, 6500 patients was calculated to be able to observe a 20% difference in mortality between the two groups with a power of 0.8.

Primary outcome was compared using a log-rank test stratified by region. Secondary outcomes were compared using the Mantel-Haenszel X² test.

A per-protocol analysis was also performed after removing all patients where the mean BIS target had not been achieved and those who had been lost to follow up.

Results

• 18,026 patients were screened, and 6644 patients were enrolled into the study. 3316 in the BIS 50 group and 3328 in the BIS 35 group
• No measurable baseline variables were found between the two groups

Accordance with protocol

• Within the ‘light’ anaesthesia group (BIS 50) then median BIS was 47.2
• Within the ‘deep’ anaesthesia group (BIS 35) the median BIS was 38.8
• The two groups were separated by an average of 8.4 BIS score, less than the 15 point difference the study was aiming for
• In 50% of the cases the anaesthetist reported difficulty with BIS tracking, in particularly in the lighter group
• 66% of the cases were within 5 units of the target (i.e. within the protocol guidelines)
• Mean arterial blood pressure (MAP) 84.5mmHg in BIS 50 group vs 81.0mmHg in BIS 35 group

Primary Outcome:

• 1-year mortality of 6.5% in BIS 50 group and 7.2% in the BIS 35 group, therefore no significant difference between the two groups

Secondary Outcomes

• No statistical difference between rates of myocardial infarction, cardiac arrest, pulmonary embolism, stroke, sepsis, surgical site infection, unplanned ICU admission, WHODAS score at 30 days and 1 year and persistent pain
• One case of awareness in BIS 50 group and none in the BIS 35 group
• Neuropathic pain at one year had similar incidence (7% BIS 50 Vs 6% BIS 35) but pain was greater in those in the BIS 35 group, which was statistically significant

Per Protocol Analysis

• No significant difference between two groups in either primary or secondary outcomes

Conclusions/Discussions

The authors have stated with the studies large sample size and well documented anaesthetic management, this study demonstrates a broad range of anaesthetic depth that can be performed safely whilst BIS monitoring is used in conjunction with volatile anaesthetic agents.

The authors “found no evidence in their data that mortality of serious complications of anaesthesia and surgery were influenced by targeting a BIS or either 35 or 50”. This evidence contrasts with previous observational studies which have suggested that deeper anaesthesia may lead to poorer outcomes, however this may have been due to confounding by lower blood pressures in their patients. During this study, mean blood pressures range were chosen by the anaesthetists prior to randomisation, with the mean values in both groups both being higher than 70mmHg.  Comparing between the two groups, the authors felt the small difference in blood pressure (4%) was unlikely to affect the results of this study. They also stated the statistically significant difference of severity, but not incidence, of neuropathic pain at one year was unlikely to be a meaningful finding.

Stated limitations of the study

• Study did not achieve their target BIS values for both groups which may have reduce the chance of observing a difference in outcomes
• 1-year mortality was lower than anticipated and therefore the study was underpowered
• Study was limited to general anaesthesia being maintained with volatile agents

Discussion for Journal Club Meeting

This was a well-run, international randomised control trial published in a well-known journal. The study was able to achieve a clinically significant difference in MAC values between the two groups (30% lower in BIS 50 group) with only one case of awareness, despite the fact 39% of patients received a MAC of less than 0.7. However, it was pointed out that this was not an age adjusted MAC and given patients were over 60, age adjusted MAC would have likely been a lot higher.

Blood pressure was maintained with an average of over 80mmHg MAP, although vasoconstrictors were used more often in the BIS 35 group.

Overall, it was difficult to make any further conclusions regarding BIS targets for these ‘high risk’ patient during major operations due to the fact that the study was unable to reach a target BIS value in either group, demonstrating the difficulty in the use of a targeted BIS range for prolonged and complicated cases. Although of note in the per protocol results similar outcomes were seen.

Summary by Dr J Blake. Journal Club Meeting 19 December 2019.