ENIGMA - Evaluation of Nitrous Oxide In the Gas Mixture for Anaesthesia: a Randomised Controlled Trial

• ClinicalTrials.gov Identifier: NCT00164047
• Recruitment Status: Completed
• First Posted: September 14, 2005
• Last Update Posted: July 31, 2009
• Sponsor: Bayside Health
• Collaborators: National Health and Medical Research Council, Australia; Australia: Theapeutic Goods Administration
• Information provided by: Bayside Health

Study Description

Brief Summary:

We aim to investigate the effectiveness and safety of nitrous oxide (N2O) in anaesthesia.

Hypothesis In patients undergoing anaesthesia for major surgery, avoidance of N2O will reduce hospital length of stay when compared with otherwise identically managed surgical patients receiving N2O as a component of their anaesthesia.

Condition or disease	Intervention/treatment	Phase
Quality of Recovery From Anaesthesia; Effects of Nitrous Oxide Following Anaesthesia; Induced Endothelial Dysfunction	Drug: Nitrous Oxide	Phase 4

Detailed Description:

There are some compelling reasons to question the routine use of nitrous oxide (N2O), also known as "laughing gas". Despite being the first anaesthetic drug introduced, and still widely used, there is sufficient doubt as to the risk-benefit profile.

There is strong evidence that N2O is a major risk factor for postoperative nausea and vomiting. It is clear that (even) brief exposure to N2O impairs methionine synthetase, an enzyme required for DNA production, red and white blood cell formation. Tissue hypoxia may be more common. These adverse effects are enhanced in "sick" patients (ie. those at highest risk, increased hospital length of stay and healthcare expenditure), and will be more likely in longer surgery. The extent of wound infection and cardiac morbidity associated with N2O is not known.

Large outcome trial data are lacking. When considering its widespread use in about 90% of all surgery around the world, small differences in outcome would have major implications for healthcare delivery. A large randomised controlled trial is necessary to answer this question.

We have recruited 2000 patients from about 25 centres around the world (mostly Australasia), who are undergoing major surgery.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 2070 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single
• Primary Purpose: Prevention
• Official Title: Evaluation of Nitrous Oxide In the Gas Mixture for Anaesthesia: a Randomised Controlled Trial
• Study Start Date: April 2003
• Actual Primary Completion Date: December 2004
• Actual Study Completion Date: December 2004

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

1. The primary endpoint is hospital length of stay (LOS), defined from the start of surgery until actual hospital discharge. Patients transferred to another hospital will be tracked until final discharge to home (or other final destination). LOS is likely

Secondary Outcome Measures :

1. Secondary endpoints will be detected by a research assistant who will be masked to Group identity, using chart review up to 30 days postoperatively; confirmation of each will be sought by an independent member of the Endpoint Committee:
2. Wound infection - if associated with purulent discharge or a positive microbial culture (46)
3. Myocardial infarction - confirmed by ECG and/or troponin or CK-MB enzyme rise
4. Venous thromboembolism - symptomatic DVT or PE, confirmed by venography, duplex ultrasonography, V-Q scan or spiral CT, or autopsy
5. Stroke - a new neurological deficit persisting for 24 hours, confirmed by neurologist assessment and/or CT scan or MRI
6. Awareness - postoperative recollection of intraoperative events
7. Blood transfusion - any red cell transfusion within 30 days of surgery
8. Pneumothorax, atelectasis, or pneumonia - confirmed by chest x-ray; for pneumonia: also 2 or more of temp> 38oC, white cell count >12,000/ml, positive sputum culture
9. Severe vomiting - at least 2 episodes >6 hrs apart, or if requiring >2 doses of antiemetic medication
10. Quality of recovery on the morning after surgery -using the validated QoR Score instrument (14), a 9-item patient-orientated measure of early postoperative health status. This is associated with patient satisfaction.
11. 30-day mortality - for safety analysis only (study not powered for this rare event).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Males and females, age 18 years and over
2. Planned general anaesthesia for surgery that includes a skin incision and expected to exceed two hours, and the patient is expected to be in hospital for at least three days

Exclusion Criteria:

1. Endoscopic or radiological procedures
2. Cardiac surgery
3. Marked impairment of gas-exchange (requiring Fi02> 0.3)
4. Thoracic surgery requiring one-lung ventilation (requiring Fi02> 0.3)
5. Specific circumstances where N2O is contraindicated (eg. volvulus, pulmonary hypertension, raised intracranial pressure)
6. Lack of provision of N2O.

Contacts and Locations

Locations

Australia, Victoria

Alfred Hospital

Melbourne, Victoria, Australia, 3004

Sponsors and Collaborators

Bayside Health

National Health and Medical Research Council, Australia

Australia: Theapeutic Goods Administration

Investigators

• Principal Investigator: Paul S Myles, MB BS MPH MD; The Alfred

More Information

Publications of Results:

Myles PS, Leslie K, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Pascoe E; ENIGMA Trial Group. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology. 2007 Aug;107(2):221-31.

Other Publications:

Myles PS, Leslie K, Silbert B, Paech MJ, Peyton P. A review of the risks and benefits of nitrous oxide in current anaesthetic practice. Anaesth Intensive Care. 2004 Apr;32(2):165-72. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Leslie K, Myles PS, Chan MT, Paech MJ, Peyton P, Forbes A, McKenzie D; ENIGMA Trial Group. Risk factors for severe postoperative nausea and vomiting in a randomized trial of nitrous oxide-based vs nitrous oxide-free anaesthesia. Br J Anaesth. 2008 Oct;101(4):498-505. doi: 10.1093/bja/aen230. Epub 2008 Aug 5.

• ClinicalTrials.gov Identifier: NCT00164047
• Other Study ID Numbers: 204/02; NHMRC 236956
• First Posted: September 14, 2005
• Last Update Posted: July 31, 2009
• Last Verified: July 2009

Keywords provided by Bayside Health:

Nitrous Oxide; Anaesthesia; Anesthesia; Recovery; Quality

Additional relevant MeSH terms:

Nitrous Oxide; Anesthetics, Inhalation; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents