Elsevier

The Lancet

Volume 394, Issue 10212, 23–29 November 2019, Pages 1907-1914
The Lancet

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

https://doi.org/10.1016/S0140-6736(19)32315-3Get rights and content

Summary

Background

An association between increasing anaesthetic depth and decreased postoperative survival has been shown in observational studies; however, evidence from randomised controlled trials is lacking. Our aim was to compare all-cause 1-year mortality in older patients having major surgery and randomly assigned to light or deep general anaesthesia.

Methods

In an international trial, we recruited patients from 73 centres in seven countries who were aged 60 years and older, with significant comorbidity, having surgery with expected duration of more than 2 h, and an anticipated hospital stay of at least 2 days. We randomly assigned patients who had increased risk of complications after major surgery to receive light general anaesthesia (bispectral index [BIS] target 50) or deep general anaesthesia (BIS target 35). Anaesthetists also nominated an appropriate range for mean arterial pressure for each patient during surgery. Patients were randomly assigned in permuted blocks by region immediately before surgery, with the patient and assessors masked to group allocation. The primary outcome was 1-year all-cause mortality. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000632897, and is closed to accrual.

Findings

Patients were enrolled between Dec 19, 2012, and Dec 12, 2017. Of the 18 026 patients screened as eligible, 6644 were enrolled, randomly assigned to treatment or control, and formed the intention-to-treat population (3316 in the BIS 50 group and 3328 in the BIS 35 group). The median BIS was 47·2 (IQR 43·7 to 50·5) in the BIS 50 group and 38·8 (36·3 to 42·4) in the BIS 35 group. Mean arterial pressure was 3·5 mm Hg (4%) higher (median 84·5 [IQR 78·0 to 91·3] and 81·0 [75·4 to 87·6], respectively) and volatile anaesthetic use was 0·26 minimum alveolar concentration (30%) lower (0·62 [0·52 to 0·73] and 0·88 [0·74 to 1·04], respectively) in the BIS 50 than the BIS 35 group. 1-year mortality was 6·5% (212 patients) in the BIS 50 group and 7·2% (238 patients) in the BIS 35 group (hazard ratio 0·88, 95% CI 0·73 to 1·07, absolute risk reduction 0·8%, 95% CI −0·5 to 2·0). Grade 3 adverse events occurred in 954 (29%) patients in the BIS 50 group and 909 (27%) patients in the BIS 35 group; and grade 4 adverse events in 265 (8%) and 259 (8%) patients, respectively. The most commonly reported adverse events were infections, vascular disorders, cardiac disorders, and neoplasms.

Interpretation

Among patients at increased risk of complications after major surgery, light general anaesthesia was not associated with lower 1-year mortality than deep general anaesthesia. Our trial defines a broad range of anaesthetic depth over which anaesthesia may be safely delivered when titrating volatile anaesthetic concentrations using a processed electroencephalographic monitor.

Funding

Health Research Council of New Zealand; National Health and Medical Research Council, Australia; Research Grant Council of Hong Kong; National Institute for Health and Research, UK; and National Institutes of Health, USA.

Introduction

Current practice for general anaesthesia involves the use of drug doses and combinations that ensure unconsciousness and suppression of potentially harmful haemodynamic responses during surgery in all patients. Patients who are sensitive to anaesthetics therefore receive more drug than necessary. With the development of processed electroencephalographic monitors such as the bispectral index (BIS), it is now possible to individualise the depth of anaesthesia.1

Using BIS as a measure of anaesthetic depth, observational studies have explored an association between increasing anaesthetic depth and mortality.2, 3, 4, 5, 6, 7, 8, 9 A meta-analysis10 of these studies revealed a 21% increase in mortality associated with deep anaesthesia. However, most of these studies did not report blood pressure, and those studies that did showed a stronger relationship between deep anaesthesia and complications when blood pressure was also low.7, 8 Several small randomised studies did not find this association between anaesthetic depth and mortality.11, 12, 13, 14, 15

Because it is unclear whether actively intervening to prevent deep anaesthesia can reduce mortality and other complications after surgery, we did the Balanced Anaesthesia Study to compare light and deep general anaesthesia in patients at risk of complications after major surgery. Our primary hypothesis was that light general anaesthesia would lead to a decrease in all-cause mortality 1 year postoperatively, compared with deep general anaesthesia.

Research in context

Evidence before this study

An association between increasing anaesthetic depth and decreased postoperative survival has been shown in observational studies; however, evidence from randomised controlled trials is required to establish causality. We searched PubMed on Aug 20, 2019, using the terms “bispectral index”, “mortality”, and “randomised controlled trial” for published randomised controlled trials comparing light general anaesthesia with deep general anaesthesia in adult patients having major surgery. Reference lists of extracted articles were manually searched for other relevant articles. Of 35 articles, we found three relevant trials, with two more found by manual searching. Two small trials (n=114 and n=200) recruited highly selected populations of patients aged 65 years and older with fractured neck of femur, one trial (n=381) was stopped after an interim analysis because of futility, mortality was a secondary outcome in one large trial of patients aged 40 years and older (n=921), and one trial (n=200) was a feasibility trial. We did not identify an adequately sized trial addressing the relationship between anaesthetic depth and mortality.

Added value of this study

In this large, international, randomised controlled trial that enrolled patients aged 60 years and older with significant comorbidity and at increased risk of complications after major surgery, we found no evidence that light general anaesthesia (bispectral index 50) was superior to deep general anaesthesia (bispectral index 35) in reducing 1-year mortality. There was one confirmed case of awareness (in the bispectral index 50 group) and no difference in cardiovascular or septic outcomes.

Implications of all the available evidence

This study provides the first adequately powered randomised comparison of light and deep anaesthesia with respect to postoperative survival. The study defines a broad range of anaesthetic depth over which anaesthesia might be safely delivered when titrating volatile anaesthetic concentrations using a processed electroencephalographic monitor. The low incidence of awareness supports the safety of targeting a bispectral index of 50 using relatively low doses of volatile anaesthetics in older patients.

Section snippets

Study design and patients

The Balanced Anaesthesia Study was an international, randomised, patient-blinded, and assessor-blinded trial comparing two levels of anaesthetic depth in older patients with significant comorbidity. The rationale, design, and pilot testing of the trial were reported previously.14, 16

We studied patients aged 60 years and older, with an American Society of Anesthesiologists (ASA) physical status of 3 or 4, who were having surgery with expected duration of more than 2 h, and an anticipated

Results

Patients were enrolled between Dec 19, 2012, and Dec 12, 2017, at 73 centres in seven countries (ie, Australia, China, Ireland, New Zealand, the Netherlands, the UK, and the USA). Of the 18 026 patients screened as eligible, 6644 were enrolled, randomly assigned to treatment or control, and formed the intention-to-treat population (3316 in the BIS 50 group and 3328 in the BIS 35 group; figure 1). The median number of patients enrolled per site was 48 (IQR 20–145); a complete list of sites and

Discussion

In this international, randomised controlled trial, we evaluated the influence of two levels of anaesthetic depth on postoperative survival and serious complications in older patients (≥60 years) with significant comorbidity presenting for major surgery. At 1 year, there was no evidence of a difference in mortality or the incidence of complications between the two groups. The quality and time course of recovery from anaesthesia and surgery were similarly unaffected.

The strengths of this study

Data sharing

Individual, deidentified participant data used in these analyses will be shared 2 years after publication by request from any qualified investigator after approval of a protocol, statistical analysis plan, and receipt of a signed data access agreement via the Research Office of Auckland District Health Board, New Zealand; and after obtaining the approval of the New Zealand Health and Disability Ethics Committees for the project and data release.

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    A complete list of sites and investigators in the Balanced Anaesthesia Study is provided in the appendix

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