Trial Outcomes & Findings for The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial (NCT NCT00430989)
NCT ID: NCT00430989
Last Updated: 2026-01-20
Results Overview
Recruitment status
COMPLETED
Study phase
PHASE4
Target enrollment
7112 participants
Primary outcome timeframe
30 days post op
Results posted on
2026-01-20
Participant Flow
Participant milestones
| Measure |
Nitrous Oxide Group
General anaesthesia containing Nitrous oxide and fraction of inspired oxygen of 30%
|
No Nitrous Oxide
General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen of 30%
|
|---|---|---|
|
Overall Study
STARTED
|
3543
|
3569
|
|
Overall Study
COMPLETED
|
3483
|
3509
|
|
Overall Study
NOT COMPLETED
|
60
|
60
|
Reasons for withdrawal
| Measure |
Nitrous Oxide Group
General anaesthesia containing Nitrous oxide and fraction of inspired oxygen of 30%
|
No Nitrous Oxide
General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen of 30%
|
|---|---|---|
|
Overall Study
Lost to Follow-up
|
2
|
3
|
|
Overall Study
Withdrawal by Subject
|
15
|
14
|
|
Overall Study
Protocol Violation
|
30
|
37
|
|
Overall Study
Not eligible
|
13
|
6
|
Baseline Characteristics
The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial
Baseline characteristics by cohort
| Measure |
N2O Group (FiO2 0.3)
n=3495 Participants
Nitrous Oxide as an inspired concentration of 70% in 30% Oxygen
|
N2O Free Group (FiO2 0.3)
n=3516 Participants
Nitrous Oxide free air and inspired Oxygen concentration of 30%
|
Total
n=7011 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
Age
|
69.2 years
STANDARD_DEVIATION 9.8 • n=37 Participants
|
69.5 years
STANDARD_DEVIATION 9.7 • n=44 Participants
|
69.3 years
STANDARD_DEVIATION 9.7 • n=40 Participants
|
|
Sex: Female, Male
Female
|
1253 Participants
n=37 Participants
|
1299 Participants
n=44 Participants
|
2552 Participants
n=40 Participants
|
|
Sex: Female, Male
Male
|
2242 Participants
n=37 Participants
|
2217 Participants
n=44 Participants
|
4459 Participants
n=40 Participants
|
|
Race/Ethnicity, Customized
Asian
|
706 participants
n=37 Participants
|
701 participants
n=44 Participants
|
1407 participants
n=40 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
19 participants
n=37 Participants
|
11 participants
n=44 Participants
|
30 participants
n=40 Participants
|
|
Race/Ethnicity, Customized
White
|
2587 participants
n=37 Participants
|
2630 participants
n=44 Participants
|
5217 participants
n=40 Participants
|
|
Race/Ethnicity, Customized
Other
|
13 participants
n=37 Participants
|
50 participants
n=44 Participants
|
63 participants
n=40 Participants
|
|
Race/Ethnicity, Customized
Indian/Pakistani
|
63 participants
n=37 Participants
|
57 participants
n=44 Participants
|
120 participants
n=40 Participants
|
|
Race/Ethnicity, Customized
Unknown
|
107 participants
n=37 Participants
|
67 participants
n=44 Participants
|
174 participants
n=40 Participants
|
PRIMARY outcome
Timeframe: 30 days post opOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
The Primary Endpoint is a Composite of Death and Cardiovascular Events (Clinical and Silent MI, Cardiac Failure, Cardiac Arrest, Pulmonary Embolism, and Stroke) Measured at 30 Days After Surgery.
|
283 participants
|
296 participants
|
SECONDARY outcome
Timeframe: 30 days post opOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
Myocardial Infarction (MI)
|
215 participants
|
219 participants
|
SECONDARY outcome
Timeframe: 30 daysOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
Cardiac Arrest
|
15 participants
|
19 participants
|
SECONDARY outcome
Timeframe: 30 Days Post opOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
Pulmonary Embolism
|
18 participants
|
22 participants
|
SECONDARY outcome
Timeframe: 30 Days Post opOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
Stroke
|
26 participants
|
19 participants
|
SECONDARY outcome
Timeframe: 30 Days Post opOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
Wound Infection
|
321 participants
|
311 participants
|
SECONDARY outcome
Timeframe: 30 Days Post OpOutcome measures
| Measure |
Nitrous Oxide: 70% N2O (FiO2 0.3)
n=3483 Participants
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
N2O Free Group (FiO2 0.3)
n=3509 Participants
N2O free group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
Nitrous Oxide: N2O 70% v's No N2O
|
|---|---|---|
|
Hospital Stay (Days)
|
6.1 Days
Interval 3.3 to 10.0
|
6.1 Days
Interval 3.3 to 10.0
|
Adverse Events
Nitrous Oxide: 70% N2O
Serious events: 283 serious events
Other events: 662 other events
Deaths: 42 deaths
Nitrous Oxide Free
Serious events: 296 serious events
Other events: 546 other events
Deaths: 57 deaths
Serious adverse events
| Measure |
Nitrous Oxide: 70% N2O
n=3483 participants at risk
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
General anaesthesia containing Nitrous oxide and fraction of inspired oxygen of 30%
|
Nitrous Oxide Free
n=3509 participants at risk
Nitrous Oxide free group (FiO2 0.3)
Nitrous Oxide: N2O 70% v's No N2O
General anaesthesia not containing Nitrous oxide and fraction of inspired oxygen of 30%
|
|---|---|---|
|
Cardiac disorders
Myocardial Infarction
|
6.2%
215/3483 • Number of events 215 • 30 Days
Adverse events do not include the primary endpoint variables
|
6.2%
219/3509 • Number of events 219 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Blood and lymphatic system disorders
Stroke
|
0.75%
26/3483 • Number of events 26 • 30 Days
Adverse events do not include the primary endpoint variables
|
0.54%
19/3509 • Number of events 19 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Cardiac disorders
Cariac Arrest
|
0.43%
15/3483 • Number of events 15 • 30 Days
Adverse events do not include the primary endpoint variables
|
0.54%
19/3509 • Number of events 19 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism
|
0.52%
18/3483 • Number of events 18 • 30 Days
Adverse events do not include the primary endpoint variables
|
0.63%
22/3509 • Number of events 22 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
General disorders
Death
|
1.2%
42/3483 • Number of events 42 • 30 Days
Adverse events do not include the primary endpoint variables
|
1.6%
57/3509 • Number of events 57 • 30 Days
Adverse events do not include the primary endpoint variables
|
Other adverse events
| Measure |
Nitrous Oxide: 70% N2O
n=3483 participants at risk
N2O Group (FiO2 0.3)
Nitrous Oxide: 70% N2O V's No N2O
General anaesthesia containing Nitrous oxide and fraction of inspired oxygen of 30%
|
Nitrous Oxide Free
n=3509 participants at risk
Nitrous Oxide free group (FiO2 0.3)
Nitrous Oxide: N2O 70% v's No N2O
General anaesthesia not containing Nitrous oxide and fraction of inspired oxygen of 30%
|
|---|---|---|
|
Nervous system disorders
Neurological
|
1.5%
53/3483 • Number of events 53 • 30 Days
Adverse events do not include the primary endpoint variables
|
1.4%
48/3509 • Number of events 48 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory
|
3.0%
103/3483 • Number of events 103 • 30 Days
Adverse events do not include the primary endpoint variables
|
2.7%
93/3509 • Number of events 93 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Gastrointestinal disorders
Gastrointestinal
|
3.0%
106/3483 • Number of events 106 • 30 Days
Adverse events do not include the primary endpoint variables
|
2.4%
85/3509 • Number of events 85 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Cardiac disorders
Cardiovascular
|
2.6%
90/3483 • Number of events 90 • 30 Days
Adverse events do not include the primary endpoint variables
|
0.71%
25/3509 • Number of events 25 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Renal and urinary disorders
Urology
|
2.1%
72/3483 • Number of events 72 • 30 Days
Adverse events do not include the primary endpoint variables
|
2.1%
73/3509 • Number of events 73 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Vascular disorders
Vascular
|
1.4%
50/3483 • Number of events 50 • 30 Days
Adverse events do not include the primary endpoint variables
|
1.1%
38/3509 • Number of events 38 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Blood and lymphatic system disorders
Bleeding complications
|
1.6%
54/3483 • Number of events 54 • 30 Days
Adverse events do not include the primary endpoint variables
|
1.6%
56/3509 • Number of events 56 • 30 Days
Adverse events do not include the primary endpoint variables
|
|
Investigations
Other
|
3.8%
134/3483 • Number of events 134 • 30 Days
Adverse events do not include the primary endpoint variables
|
3.6%
128/3509 • Number of events 128 • 30 Days
Adverse events do not include the primary endpoint variables
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place