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The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial

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ClinicalTrials.gov Identifier: NCT00430989
Recruitment Status : Completed
First Posted : February 2, 2007
Results First Posted : June 17, 2019
Last Update Posted : December 4, 2019
Sponsor:
Collaborator:
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Bayside Health

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Outcomes Assessor);   Primary Purpose: Treatment
Condition Coronary Artery Disease
Interventions Other: Nitrous Oxide
Other: No Nitrous Oxide
Enrollment 7112
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Nitrous Oxide Group No Nitrous Oxide
Hide Arm/Group Description General anaesthesia containing Nitrous oxide and fraction of inspired oxygen of 30% General anaesthesia not containing Nitrous oxide with fraction of inspired oxygen of 30%
Period Title: Overall Study
Started 3543 3569
Completed 3483 3509
Not Completed 60 60
Reason Not Completed
Lost to Follow-up             2             3
Withdrawal by Subject             15             14
Protocol Violation             30             37
Not eligible             13             6
Arm/Group Title N2O Group (FiO2 0.3) N2O Free Group (FiO2 0.3) Total
Hide Arm/Group Description Nitrous Oxide as an inspired concentration of 70% in 30% Oxygen Nitrous Oxide free air and inspired Oxygen concentration of 30% Total of all reporting groups
Overall Number of Baseline Participants 3495 3516 7011
Hide Baseline Analysis Population Description
Of 10 102 eligible patients, 7112 patients were enrolled and randomly assigned: 3543 to receive nitrous oxide and 3569 not to receive nitrous oxide; 7011 patients underwent induction of anaesthesia and were included at baseline, and 6992 patients were assessed for the primary endpoint (figure 1).
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Age Number Analyzed 3495 participants 3516 participants 7011 participants
69.2  (9.8) 69.5  (9.7) 69.3  (9.7)
[1]
Measure Description: AGE>18
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3495 participants 3516 participants 7011 participants
Female
1253
  35.9%
1299
  36.9%
2552
  36.4%
Male
2242
  64.1%
2217
  63.1%
4459
  63.6%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3495 participants 3516 participants 7011 participants
Asian 706 701 1407
Black or African American 19 11 30
White 2587 2630 5217
Other 13 50 63
Indian/Pakistani 63 57 120
Unknown 107 67 174
1.Primary Outcome
Title 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.
Hide Description [Not Specified]
Time Frame 30 days post op
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Nitrous Oxide: 70% N2O (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:

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)

Nitrous Oxide: 70% N2O V's No N2O

Nitrous Oxide: N2O 70% v's No N2O

Overall Number of Participants Analyzed 3483 3509
Measure Type: Number
Unit of Measure: participants
283 296
2.Secondary Outcome
Title Myocardial Infarction (MI)
Hide Description [Not Specified]
Time Frame 30 days post op
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Nitrous Oxide: 70% N2O (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:

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)

Nitrous Oxide: 70% N2O V's No N2O

Nitrous Oxide: N2O 70% v's No N2O

Overall Number of Participants Analyzed 3483 3509
Measure Type: Number
Unit of Measure: participants
215 219
3.Secondary Outcome
Title Cardiac Arrest
Hide Description [Not Specified]
Time Frame 30 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Nitrous Oxide: 70% N2O (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:

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)

Nitrous Oxide: 70% N2O V's No N2O

Nitrous Oxide: N2O 70% v's No N2O

Overall Number of Participants Analyzed 3483 3509
Measure Type: Number
Unit of Measure: participants
15 19
4.Secondary Outcome
Title Pulmonary Embolism
Hide Description [Not Specified]
Time Frame 30 Days Post op
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N2O Group (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:
N2O Group (FiO2 0.3)
N2O free group (FiO2 0.3)
Overall Number of Participants Analyzed 3483 3509
Measure Type: Number
Unit of Measure: participants
18 22
5.Secondary Outcome
Title Stroke
Hide Description [Not Specified]
Time Frame 30 Days Post op
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Nitrous Oxide: 70% N2O (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:

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)

Nitrous Oxide: 70% N2O V's No N2O

Nitrous Oxide: N2O 70% v's No N2O

Overall Number of Participants Analyzed 3483 3509
Measure Type: Number
Unit of Measure: participants
26 19
6.Secondary Outcome
Title Wound Infection
Hide Description [Not Specified]
Time Frame 30 Days Post op
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Nitrous Oxide: 70% N2O (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:

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)

Nitrous Oxide: 70% N2O V's No N2O

Nitrous Oxide: N2O 70% v's No N2O

Overall Number of Participants Analyzed 3483 3509
Measure Type: Number
Unit of Measure: participants
321 311
7.Secondary Outcome
Title Hospital Stay (Days)
Hide Description [Not Specified]
Time Frame 30 Days Post Op
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Nitrous Oxide: 70% N2O (FiO2 0.3) N2O Free Group (FiO2 0.3)
Hide Arm/Group Description:

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)

Nitrous Oxide: 70% N2O V's No N2O

Nitrous Oxide: N2O 70% v's No N2O

Overall Number of Participants Analyzed 3483 3509
Median (Inter-Quartile Range)
Unit of Measure: Days
6.1
(3.3 to 10)
6.1
(3.3 to 10)
Time Frame 30 Days
Adverse Event Reporting Description Adverse events do not include the primary endpoint variables
 
Arm/Group Title Nitrous Oxide: 70% N2O Nitrous Oxide Free
Hide Arm/Group Description

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 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%

All-Cause Mortality
Nitrous Oxide: 70% N2O Nitrous Oxide Free
Affected / at Risk (%) Affected / at Risk (%)
Total   42/3483 (1.21%)      57/3509 (1.62%)    
Hide Serious Adverse Events
Nitrous Oxide: 70% N2O Nitrous Oxide Free
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   283/3483 (8.13%)      296/3509 (8.44%)    
Blood and lymphatic system disorders     
Stroke  1  26/3483 (0.75%)  26 19/3509 (0.54%)  19
Cardiac disorders     
Myocardial Infarction  1  215/3483 (6.17%)  215 219/3509 (6.24%)  219
Cariac Arrest  1  15/3483 (0.43%)  15 19/3509 (0.54%)  19
General disorders     
Death  1  42/3483 (1.21%)  42 57/3509 (1.62%)  57
Respiratory, thoracic and mediastinal disorders     
Pulmonary Embolism  1  18/3483 (0.52%)  18 22/3509 (0.63%)  22
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Nitrous Oxide: 70% N2O Nitrous Oxide Free
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   662/3483 (19.01%)      546/3509 (15.56%)    
Blood and lymphatic system disorders     
Bleeding complications  1  54/3483 (1.55%)  54 56/3509 (1.60%)  56
Cardiac disorders     
Cardiovascular  1  90/3483 (2.58%)  90 25/3509 (0.71%)  25
Gastrointestinal disorders     
Gastrointestinal  1  106/3483 (3.04%)  106 85/3509 (2.42%)  85
Investigations     
Other  1 [1]  134/3483 (3.85%)  134 128/3509 (3.65%)  128
Nervous system disorders     
Neurological  1  53/3483 (1.52%)  53 48/3509 (1.37%)  48
Renal and urinary disorders     
Urology  1  72/3483 (2.07%)  72 73/3509 (2.08%)  73
Respiratory, thoracic and mediastinal disorders     
Respiratory  1  103/3483 (2.96%)  103 93/3509 (2.65%)  93
Vascular disorders     
Vascular  1  50/3483 (1.44%)  50 38/3509 (1.08%)  38
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
[1]
All other events less than 2% overall
All 'other' adverse events the events were classed according to system MedDRA reporting and not by individual event.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Professor Paul Myles
Organization: Bayside health
Phone: +61390762000 ext 3176
EMail: p.myles@alfred.org.au
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Beattie WS, Wijeysundera DN, Chan MTV, Peyton PJ, Leslie K, Paech MJ, Sessler DI, Wallace S, Myles PS, Galagher W, Farrington C, Ditoro A, Baulch S, Sidiropoulos S, Bulach R, Bryant D, O'Loughlin E, Mitteregger V, Bolsin S, Osborne C, McRae R, Backstrom M, Cotter R, March S, Silbert B, Said S, Halliwell R, Cope J, Fahlbusch D, Crump D, Thompson G, Jefferies A, Reeves M, Buckley N, Tidy T, Schricker T, Lattermann R, Iannuzzi D, Carroll J, Jacka M, Bryden C, Badner N, Tsang MWY, Cheng BCP, Fong ACM, Chu LCY, Koo EGY, Mohd N, Ming LE, Campbell D, McAllister D, Walker S, Olliff S, Kennedy R, Eldawlatly A, Alzahrani T, Chua N, Sneyd R, McMillan H, Parkinson I, Brennan A, Balaji P, Nightingale J, Kunst G, Dickinson M, Subramaniam B, Banner-Godspeed V, Liu J, Kurz A, Hesler B, Fu AY, Egan C, Fiffick AN, Hutcherson MT, Turan A, Naylor A, Obal D, Cooke E; ANZCA Clinical Trials Network for the ENIGMA-II Investigators. Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial. Anesth Analg. 2018 Nov;127(5):1118-1126. doi: 10.1213/ANE.0000000000003310.
Layout table for additonal information
Responsible Party: Bayside Health
ClinicalTrials.gov Identifier: NCT00430989    
Other Study ID Numbers: 6/07
First Submitted: January 31, 2007
First Posted: February 2, 2007
Results First Submitted: February 16, 2016
Results First Posted: June 17, 2019
Last Update Posted: December 4, 2019