(EBM) Enigma-I trial





Anesthesiology 2007; 107:221-31

Background

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

"Avoidance of Nitrous oxide for patients undergoing major surgery"

Published in Anesthesiology 2007

Question: Whether avoidance of nitrous oxide (thus allowing increased FiO2) could decrease duration of hospital stay after surgery and reduce complications, compared to a nitrous-oxide based anesthetic regmin, in adults undergoing major surgery

Method

  • Multi-centered prospective, single-blinded, RCT
    • 19 hospitals
    • Only anaesthetist is NOT blinded

Groups

  • N2O-free group
  • N2O 70% + O2 30% group

Inclusion criteria

  • Adult
  • Major surgery anticipated to exceed 2 hours
  • Expected to be in hospital for at least 3 days after surgery

Exclusion

  • Cardiac surgery
  • Thoracic surgery requiring one-lung ventilation
  • If anaesthetist considered N2O was contraindicated

Outcome

Primary outcome

Duration of hospital stay

Secondary outcome

Postop complications

  • Wound infection
  • Pneumonia
  • Fever
  • Atelectasis
  • Pneumothorax
  • Severe PONV
  • MI
  • Stroke
  • Awareness
  • Venous thromboembolism
  • Blood transfusion

Composite endpoints

  • Any respiratory complications
    • Pneumonia
    • Atelectasis
    • Pneumothorax
    • PE
  • Any major complications
    • Pneumonia
    • Pneumothorax
    • PE
    • Wound infection
    • MI
    • Stroke
    • Venous thromboembolism
    • Awareness
    • Death within 30 days

Secondary analyses

Effects of using different FiO2 in NO2-free group

Design

  • 90% power (type II error of 0.1)
  • Two sided alpha of 0.05
  • Aim to detect a reduction of mean duration of hospital stay
    ... from 4 days to 3.5 days (SD = 3 days)
  • Expected sample size 2000
  • Would also have 77% power to detect a decrease in wound infection rate from 14% to 10%

Findings

  • n = 2012
    • 997 in N2O-free group
    • 1015 in N2O group

Primary end-point

  • Median duration of hospital stay
    • 7.0 days in N2O-free group
    • 7.1 days in N2O group

Others

N2O-free group...

  • More likely to be out of hospital
    • Hazard ratio = 1.09
    • 95% CI 1.00 to 1.19
    • p = 0.06
  • More likely to be out of ICU
    • Hazard ratio = 1.35
    • 95% CI 1.05 to 1.73
    • p = 0.02
  • More likely to have better recovery scores
    • p = 0.042
  • Lower incidence of severe PONV
    • 10% (vs 23%)
    • OR = 0.40
    • 95% CI 0.31 to 0.51
    • p < 0.001
  • Less wound infection
    • 7.7% (vs 10%)
    • OR = 0.72
    • 95% CI 0.53 to 0.98
    • p = 0.034
  • Less fever
    • 28% (vs 34%)
    • OR = 0.74
    • 95% CI 0.61 to 0.89
    • p = 0.002
  • Less pneumonia
    • 1.5% (vs 3%)
    • OR = 0.50
    • 95% CI 0.27 to 0.94
    • p = 0.031
  • Less atelectasis
    • 7.5% (vs 13%)
    • OR = 0.57
    • 95% CI 0.42 to 0.77
    • p < 0.001
  • Less likely to have any pulmonary complications
    • 7.8% (vs 13%)
    • OR = 0.57
    • 95% CI 0.42 to 0.76
    • p < 0.001
  • Less likely to have at least one major complication
    • 16% (vs 21%)
    • OR = 0.71
    • 95% CI 0.56 to 0.89
    • p = 0.003

Other findings (NOT statistically significant)

N2O-free group...

  • Less MI (non-significant)
    • 0.7% vs 1.3%
    • OR = 0.54
    • p = 0.20
    • p = 0.26 (adjusted)
  • Less death within 30 days (non-significant)
    • 0.3% vs 0.9%
    • OR = 0.34
    • p = 0.10
    • p = 0.096 (adjusted)

Others

  • N2O-free group

    • More likely to received TIVA
      • 19% (vs 13%)
    • More likely to be eligible for discharge from PACU
      • No difference in time to eye-opening

  • N2O group

    • use 23% less volatile agents

  • No evidence of difference in awareness

    • But not powered to find a difference

Secondary analysis

  • Higher FiO2 is associated with reduction in fever (p < 0.001)

  • No difference in other outcomes

Limitation

  • May not be extrapolated to

    • Minor surgeries
    • Paediatric surgeries

  • Multiple comparisons

    • Increased risk of type I error (i.e. false positive)

Others

  • No clinically meaningful difference in hospital stay duration

    • Maybe some postop complications are transient
      ... thus does not affect hospital stay

  • The difference in end-points between groups may be due to:

    • N2O avoidance
    • Use of high FiO2

Effect on B12 metabolism

  • Exposure to N2O for a few hours will

    • Reduce methionine synthase activity by 50%
    • Can lead to significant vitamin B12 and folate deficiency

  • Preop folate or vitamin B supplementation doesn't seem to make any difference

Follow-up study

ENIGMA II trial is commenced due to the finding of increased MI and death

Even though not significant statistically, it would be very clinically significant if true

Pragmatic vs explanatory

Enigma-I (and II) trial was a "pragmatic" trial

  • i.e. To compare impacts of different managements in routine clinical settings
  • NOT "explanatory" trial, which would be to establish causal relationships
    • e.g. A causes B, C, and D, but not E nor F

Some critics have argued that Enigma was a pragmatic trial, thus should not have been analysed like an explanatory trial.