The ENIGMA-II Trial
Evaluation of NItrous oxide in the Gas Mixture for Anaesthesia “Nitrous Oxide Anaesthesia and Cardiac Morbidity after Major Surgery”
Trial steering committee and chief investigators
Paul Myles, Kate Leslie, Phil Peyton, Andrew Forbes, Phil Peyton, Brendan Silbert, Michael Paech, Matthew Chan, PJ Devereaux (Canada), and Dan Sessler (USA)
There are about 20
million anaesthetics given each year in the US (1:10 of the population), with
the majority receiving N2O. Approximately 25% of patients undergoing
major surgery have known coronary artery disease (CAD) or risk factors for
CAD. In 1990, approximately 1 million of
the 25 million Americans who underwent noncardiac surgery suffered a
perioperative cardiac event, resulting in $20 billion in costs.
N2O
interferes with vitamin B12 and folate metabolism. This impairs production of
methionine (from homocysteine), used to form tetrahydrofolate and thymidine
during DNA synthesis. It has been repeatedly demonstrated that N2O anaesthesia increases
postoperative homocysteine levels. Chronic hyperhomocysteinaemia is associated
with cardiovascular disease, and acute hyperhomocysteinaemia is known to cause
endothelial dysfunction. One small trial has demonstrated an increased
incidence of postoperative myocardial ischaemia in patients receiving N2O anaesthesia. Reducing postoperative myocardial infarction
and death are important aims for those with CAD undergoing major surgery.
Our previous trial (ENIGMA I) studied 2050 patients and
identified some serious adverse effects, but most patients were not at risk of
CAD and so we could not reliably assess serious cardiac complications. The next phase of this study ENIGMA II (a
large simple multicentre randomized controlled trial) will evaluate the
efficacy of removing N2O
from the anaesthetic in moderate and high risk patients undergoing non-cardiac
surgery.
TRIAL SUMMARY
Hypothesis
Avoidance of N2O will reduce the incidence of a composite endpoint of death, MI,
cardiac arrest, PE and stroke from 8% to 6% at 30 days.
Study Design
Large, multi-centre, randomised, blinded, clinical trial. 7000
high risk cardiac patients undergoing major non-cardiac surgery will be
randomly allocated to either a N2O-containing (70% N2O in
oxygen) or N2O-free (nitrogen in oxygen) anaesthetic; both groups
FiO2 0.3. Patients, surgeons,
and nursing staff, and all individuals responsible for all outcome assessments
will be blinded.
7,000 non-cardiac patients having surgery >2 hrs duration
Randomised, controlled double-blind trial
3,500 patients 3,500 patients
N2O 70% and O2 30% N2O 0% and O2 30%
ECGs (pre-op, day 1-3)
Troponins (6-12hr, day1-3)
Record review and interview day 30
The primary endpoint is a composite of death and cardiovascular events (clinical and silent MI, cardiac arrest, pulmonary embolism, and stroke) measured at 30 days after surgery.
If you would like further information regarding the trial or
are interested in being a site investigator please contact
email:
enigma2@admin.org.au
You can also find further information about the trial on the ENIGMA II website www.enigma2.org.au
The ENIGMA Trial was
funded by the NHMRC, Australian & New Zealand College of Anaesthetists,
Health and Health Services Research Fund (Hong Kong), and the
Alfred Hospital Research Trust
