1. Cost-benefit analysis of nitrous oxide in major surgery Presenter: Dr Alison Graham 2 nd year Anaesthesia Advanced Trainee Co-Authors: Prof Paul S. Myles, Prof. Kate Leslie, Prof. Matthew T.V. Chan, Prof. Michael J. Paech, Dr Philip Peyton and Prof. Abdelazeem A. El. Dawlatly

2. Topics: Review ENIGMA trial Cost-benefit analysis –Methods –Results –Limitations –Conclusion

3. ENIGMA Trial The Avoidance of Nitrous Oxide in Major Surgery What are the consequences of using nitrous oxide? 80% O 2 & 20% N 2 30% O 2 & 70% N 2 O VS

4. ENIGMA Results VariableNitrous-oxide free group Nitrous-oxide group p-value Hospital LOS, days (IQR) 7.0 (4.0 – 10.9)7.1 (4.0 – 11.8)0.06 Time to eligibility to discharge from PACU, minutes median (IQR) 84 (64 – 120)92 (65 – 125)0.02 ICU admissions, No. (%) 122 (12%)140 (14%)0.3

5. ENIGMA Trial Results Kaplan-Meier estimates of discharge from the intensive care unit

6. ENIGMA Results VariableNitrous oxide- free Group No. (%) Nitrous oxide Group No. (%) Adjusted Odds Ratio (95% CI) p-value Severe nausea or vomiting 104 (10)229 (23)0.40 (0.31-0.51)<0.001 Wound infection 77 (7.7)106 (10)0.72 (0.52-0.98)0.036 Fever 275 (28)345 (34)0.73 (0.60-0.90)0.003 Pneumonia 15 (1.5)30 (3.0)0.51 (0.27-0.97)0.040 Atelectasis 75 (7.5)127 (13)0.55 (0.40-0.75)<0.001 Pneumothorax 1 (0.1)3 (0.3)-- Myocardial infarction 7 (0.7)13 (1.3)0.58 (0.22-1.50)0.26 Thromboembolism 16 (1.6)10 (1.0)1.60 (0.72-3.55)0.25 Blood transfusion 188 (19)202 (20)0.96 (0.75-1.21)0.71 Stroke 1 (0.1) -- Awareness 0 (0.0)2 (0.2)-- Death within 30 days 3 (0.3)9 (0.9)0.33 (0.09-1.22)0.096

7. ENIGMA Results VariableNitrous oxide- free Group No. (%) Nitrous oxide Group No. (%) Adjusted Odds Ratio (95% CI) p-value Severe nausea or vomiting 104 (10)229 (23)0.40 (0.31-0.51)<0.001 Wound infection 77 (7.7)106 (10)0.72 (0.52-0.98)0.036 Fever 275 (28)345 (34)0.73 (0.60-0.90)0.003 Pneumonia 15 (1.5)30 (3.0)0.51 (0.27-0.97)0.040 Atelectasis 75 (7.5)127 (13)0.55 (0.40-0.75)<0.001 Pneumothorax 1 (0.1)3 (0.3)-- Myocardial infarction 7 (0.7)13 (1.3)0.58 (0.22-1.50)0.26 Thromboembolism 16 (1.6)10 (1.0)1.60 (0.72-3.55)0.25 Blood transfusion 188 (19)202 (20)0.96 (0.75-1.21)0.71 Stroke 1 (0.1) -- Awareness 0 (0.0)2 (0.2)-- Death within 30 days 3 (0.3)9 (0.9)0.33 (0.09-1.22)0.096

8. Criticism of the ENIGMA Trial “ Despite the concerns regarding its adverse effects, nitrous oxide has actually had a central position in anesthetic practice primarily because it is inexpensive, widely available, and has a long-standing safety profile. The most obvious advantage of using nitrous oxide is that it allows a dose reduction of other anesthetic agents and opioids, which translates into less cardiovascular depression and significant cost reduction” Anesthesiology 2008; 108:541-2

9. Cost-Benefit Analysis of the ENIGMA Trial What is the financial cost of using nitrous oxide?

10. Health economics

11. Cost Minimisation Cost benefit - $ only Cost effectiveness – natural units Cost utility - QALY Health economics

12. Cost-Benefit Analysis of the ENIGMA Trial What is the financial cost of using nitrous oxide? From the hospital administration’s point of view

13. Cost-benefit N 2 O: variable costs Costs saved –Maintenance anaesthetic –Analgesia –Vasopressors Expenses –PONV prophylaxis –PONV –Infection/fever –Pneumonia –Atelectasis –PACU –ICU –HLOS

14. Cost-benefit N 2 O: variable costs Costs saved –Maintenance anaesthetic –Analgesia –Vasopressors Expenses –PONV prophylaxis –PONV –Infection/fever –Pneumonia –Atelectasis –PACU –ICU –HLOS

15. Contributing Cost Estimates Contributing cost descriptionEstimated cost per unit (2010 US dollars) Gas supplies: nitrous oxide$0.0123/L oxygen and medical air$0.003/L Induction agents: Propofol$1.40 per 200 mg ampoule Thiopentone$12.60 per 500 mg ampoule Inhalational agents: Sevoflurane$11.40 MAC hour Isoflurane$1.50 MAC hour Desflurane$12.60 MAC hour Prophylactic antiemetic therapy:$4.95 per treatment

16. Contributing Cost Estimates Contributing cost description Estimated cost per unit (2010 US dollars) Number of studies PACU stay$0.81/minute3 PONV $22.56 for 1 or more episodes 7 Wound infection$10,514/infection30 Pneumonia$13,439/infection9 ICU stay $2,110/day11

17. ENIGMA Cost-Benefit Analysis: Results Nitrous oxide-free Group (n = 997) Nitrous oxide Group (n = 1,015) p-value Anaesthetic drugs 27 ± 2226 ± 220.16 Bed days12,793 ± 11,54714,685 ± 18,7180.005 Complications1,017 ± 3,4961,500 ± 4,2100.006 Total costs13,837 ± 13,25616,203 ± 20,8420.002 Estimated costs per patient (US dollars), Mean ± SD

18. ENIGMA Cost-Benefit Analysis: Sensitivity Analysis Nitrous oxide- free group (n = 997) Nitrous oxide group (n = 1,015) p-value Total estimated costs (base line)13,837 ± 13,25616,203 ± 20,8420.002 ¼ of component costs (i) Wound infection13,228 ± 12,42115,379 ± 19,9020.004 (ii) Pneumonia13,686 ± 12,73415,915 ± 20,1360.003 (iii) Bed days4,242 ± 5,3015,187 ± 7,4870.001 4x component costs (i) Wound infection16,273 ± 18,71219,500 ± 26,5360.002 (ii) Pneumonia14,444 ± 16,12717,356 ± 24,6310.002 (iii) Bed days52,218 ± 47,60460,269 ± 76,7650.005 Estimated costs per patient (US dollars), Mean ± SD

19. Cost-Benefit Analysis Limitations Estimated costs (but the statistics are real) Hospital perspective only Use of published estimates of costs –Precedent studies mostly from developed countries –No discrimination on methods Variable costs only included PACU costs controversial

20. Conclusions There are significant additional costs with N 2 O use No compelling argument to use N 2 O on the basis that it is an inexpensive drug

21. Questions

23. Sensitivity Analysis Nitrous oxide- free Group (n = 997) Nitrous oxide Group (n = 1,015) P value Total estimated costs (US dollars), Mean ± SD 13,837 ± 13,25616,203 ± 20,8420.002 ¼ of costs from main analysis: i. Wound infection13,228 ± 12,42115,379 ± 19,9020.004 ii. Pneumonia13,686 ± 12,73415,915 ± 20,1360.003 iii. Bed days4,242 ± 5,3015,187 ± 7,4870.001 4x costs from main analysis: i. Wound infection16,273 ± 18,71219,500 ± 26,5360.002 ii. Pneumonia14,444 ± 16,12717,356 ± 24,6310.002 iii. Bed days52,218 ± 47,60460,269 ± 76,7650.005 Cost estimates if including non- statistically significant complications 13,890 ± 13,59516,303 ± 21,0380.002