(EBM) Enigma-II trial





TL;DR: N2O does NOT increase the risk of death or CVS events in at-risk patients.

A. Background

ENIGMA = Evaluation of Nitrous oxide In the Gas Mixture for Anaesthesia

Published: The Lancet vol 384, issue 9952, pp 1446 -1454

Question: Does addition of N2O to anaesthetic regimen increase occurrence of death and CVS complications in at-risk patients having non-cardiac surgery?

Enigma-I

Enigma-I study published in 2007 found that the N2O avoidance group had:

  • Less MI (non-significant)
    • OR = 0.54
    • p = 0.20
  • Less death within 30 days (non-significant)
    • OR = 0.34
    • p = 0.10

Thus Enigma-II trial was launched to see if use of N2O increases periop CVS and mortality risk

B. Method

Design

  • Prospective, multicentre, randomised controlled trial
  • Everyone except the attending anaesthetist was blinded
    • i.e. patients, surgical team, postop interviewer, and end-point adjudicators were blinded

Inclusion criteria

  • Adults ≥ 45 years old
  • Surgery
    • Non-cardiac surgery
    • Under GA
    • Expected to last more than 2 hours
  • Increased risk of cardiac events
    • Coronary artery disease
      • Angina
      • MI
      • Segmental wall motion abnormality on echo or a fixed defect on radionuclide imaging
      • Positive exercise stress test for cardiac ischaemia
      • Positive radionuclide exercise, echo exercise, or pharmacological stress test for cardiac ischaemia
      • Coronary revascularisation (CABG or PTCA)
      • Angiographic evidence of atherosclerosis stenosis ≥ 50% of any coronary artery
      • ECG with pathological Q waves in 2 contiguous leads
    • Heart failure
    • Cerebrovascular disease due to atherothrombotic disease
    • Undergoing aortic or peripheral vascular surgery
    • Or 3 or more of the following
      • Age ≥ 70 yo
      • Any history of congestive heart failure
      • DM on any Rx
      • Current treatment for HTN
      • Preop creatinine > 175 µmol/L
      • Current or previous high total cholesterol ≥ 6.2 mmol/L
      • Emergency / urgent surgery (surgery within 24 h of acute presentation to hospital)
      • High risk surgery (intrathoracic or intraperitoneal)

Exclusion criteria

  • Having cardiac surgery
  • Expected to require FiO2 > 0.5 intraoperatively
    • Marked impairment of gas-exchange
    • One-lung ventilation
  • Special cases where N2O is contraindicated
    • Volvulus
    • Pulmonary hypertension
    • Raised intracranial pressure
  • N2O is unavailable for use

Additionally in the final paper:

  • Patients at high risk of postop emesis

Study groups / arms

Two groups:

  • Nitrous group (N2O 70% + O2 30%)
  • No N2O group (N2 70% + O2 30%)

End-points

Primary end-point:

During the initial 30 days postop...

  • Death
  • Cardiovascular events
    • Non-fatal MI
    • Cardiac arrest
    • Pulmonary embolism
    • Stroke

Secondary end-points:

  • Non-fatal MI
  • Surgical site infection

Tertiary end-points:

  • All-cause mortality
  • Stroke
  • Pulmonary embolism
  • Cardiac arrest
  • Severe PONV
  • Duration of stay in PACU
  • Unplanned admission to ICU
  • Duration of mechanical ventilation
    • Used as a proxy measure for ICU stay
  • Duration of hospital stay
  • Overall quality of recovery

➤ Severe PONV is defined by:

  • Occurrence of at least 2 episodes of severe nausea or vomiting more than 6 hours apart
  • If patient needed more than two doses of any anti-emetic drugs

Statistical analysis

7000 patient would be needed to detect a reduction in primary outcome from 8% to 6%, with a type I error of 0.05 and type II error of 0.1

All reported p values are two-sided and NOT adjusted for multiple comparisons

Funding

Grants were from Australian NHMRC, ANZCA, Heart and Stroke Foundation of Quebec and Ontario, General Research Fund of the Research Grant Council, Hong Kong

Committees

  • Steering committee
  • Data quality committee
  • Data and safety committee
  • Independent endpoint adjudication committee

Sites recruiting 35 or more participants were independently audited.

C. Findings

Numbers

  • 45 participating centres from ten countries
  • Patients enrolled between 2008-05-30 and 2013-09-28
    • 12140 patients undergoing > 2 hour surgery under GA
    • 10102 eligible
    • 7112 patients enrolled and randomised
      • 3543 to receive N2O
      • 3569 to NOT receive N2O
    • 7011 patients had surgery
      • 3495 in N2O group
      • 3516 in No N2O group
    • 6992 patients assessed for primary endpoints
      • 3483 in N2O group
      • 3509 in No N2O group

Baseline characteristics

Overall demographic, dietary, medical, and periop characteristics at baseline were similar between the two groups.

Outcome

Primary outcome

Death or CVS complications in first 30 days postop:

  • N2O group: 283 (8%)
  • NN group: 296 (8%)
  • RR = 0.96, 95% CI 0.83 to 1.12, p=0.64

Secondary outcome:

No statistically significant differences in surgical site infection and in the rate of MI

⦿ NB:

  • SSI rate in Enigma-II ≈ 9%
  • SSI rate in Enigma-I ≈ 9% overall (7.7% in N2O-free group, 10.4% in N2O group)

Tertiary outcome:

No statistically significant differences, except for PONV and patient-rated quality of recovery scores

  • Severe PONV within 3 days postop

    • N2O group: 506 (15%)
    • NN group: 378 (11%)
    • RR = 1.35, 95% CI 1.19 to 1.53, p < 0.0001

  • Effects of prophylactic anti-emetics

    • If prophylactic antiemetics given,
      • RR = 1.12
      • 95% CI 0.95 to 1.32
    • If prophylactic antiemetic not given,
      • RR = 1.75
      • 95% CI 1.43 to 2.13

  • Mean patient-rated quality of recovery scores is lower in N2O group

    • 12.7 vs 13.0
    • p < 0.0001

Interaction between primary outcomes in two groups, and patient characteristics

The primary outcome were not statistically different between the two group, across different subgroups (e.g. age, gender, ASA, hospital, vascular vs non-vascular, regional vs no regional)

D. Other notes

Comparison with the original Enigma study

Design

  • Patients with high risk PONV were excluded from the study
    • i.e. actual difference in PONV could have been even larger
    • No such exclusion criteria in the original study
  • Pulmonary complications not tracked

Patient-related

Baseline differences in Enigma-II, compared to the original Enigma study:

  • Age
    • Mean age: 69.4 years old (vs 55.2 yo)
    • 65 years or older: 66.6% (vs 30.5%)
  • More men: 63.6% vs 52.3%
  • Higher ASA scores
    • ASA 1: <1% (vs 20.6%)
    • ASA 2: 31% (vs 54.9%)
    • ASA 3: 61.5% (vs 23.4%)
    • ASA 4: 7% (vs 1%)
  • PONV score
    • 0: 7.3% (vs 6.3%)
    • 1: 34.4% (vs 30.0%)
    • 2: 42.3% (vs 39.1%)
    • 3: 15.5% (vs 21.6%)
    • 4: 0.4% (vs 3.1%)

⦿ NB:

  • Focus was on patients with significant cardiac risk factors

Surgery-related

Types of surgery:

  • Emergency surgery: 4% (vs 4%)
  • Contaminated or dirty: 18.6% (vs 34.5%)
  • Colorectal: 4.8% (vs 14.9%)
  • General: 20.1% (vs 45.7%)
  • Vascular: 38.8% (vs 4.2%)
  • Orthopedic: 13.7% (vs 9.5%)

Duration:

  • Duration of surgery: 2.6hr (vs 3.3 h)
  • Duration of anaesthesia: 3.2hr (vs 3.7 h)

Anaesthetic-related

  • Antiemetics

    • Used more often in the N2O group
      • 60% in N2O group vs 55% (p < 0.0001)
      • No difference in Enigma-I
    • Used more often overall
      • Used in 57.4% (vs 34.7%)

  • Enigma-II uses FiO2 of 0.3 for both groups

    • c.f. the original Enigma uses FiO2 of 0.3 for N2O group, and FiO2 of 0.8 (median) for the NN group

Intervention

  • 17% of patients in each group were admitted to ICU or HDU immediately after surgery
  • Prophylactic antiemetic is given more often in N2O group
    • 60% vs 55%, p < 0.0001
  • Slightly higher FiO2 is used in NN group
    • FiO2 of 33% vs 30%, p < 0.0001
  • Slight differences in HR, SBP, and O2
    • Statistically significant but not clinically significant