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

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

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

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

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

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 ( )<0.001 Wound infection 77 (7.7)106 (10)0.72 ( )0.036 Fever 275 (28)345 (34)0.73 ( )0.003 Pneumonia 15 (1.5)30 (3.0)0.51 ( )0.040 Atelectasis 75 (7.5)127 (13)0.55 ( )<0.001 Pneumothorax 1 (0.1)3 (0.3)-- Myocardial infarction 7 (0.7)13 (1.3)0.58 ( )0.26 Thromboembolism 16 (1.6)10 (1.0)1.60 ( )0.25 Blood transfusion 188 (19)202 (20)0.96 ( )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 ( )0.096

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 ( )<0.001 Wound infection 77 (7.7)106 (10)0.72 ( )0.036 Fever 275 (28)345 (34)0.73 ( )0.003 Pneumonia 15 (1.5)30 (3.0)0.51 ( )0.040 Atelectasis 75 (7.5)127 (13)0.55 ( )<0.001 Pneumothorax 1 (0.1)3 (0.3)-- Myocardial infarction 7 (0.7)13 (1.3)0.58 ( )0.26 Thromboembolism 16 (1.6)10 (1.0)1.60 ( )0.25 Blood transfusion 188 (19)202 (20)0.96 ( )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 ( )0.096

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

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

Health economics

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

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

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

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

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

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

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

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, ¼ of component costs (i) Wound infection13,228 ± 12,42115,379 ± 19, (ii) Pneumonia13,686 ± 12,73415,915 ± 20, (iii) Bed days4,242 ± 5,3015,187 ± 7, x component costs (i) Wound infection16,273 ± 18,71219,500 ± 26, (ii) Pneumonia14,444 ± 16,12717,356 ± 24, (iii) Bed days52,218 ± 47,60460,269 ± 76, Estimated costs per patient (US dollars), Mean ± SD

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

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

Questions

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, ¼ of costs from main analysis: i. Wound infection13,228 ± 12,42115,379 ± 19, ii. Pneumonia13,686 ± 12,73415,915 ± 20, iii. Bed days4,242 ± 5,3015,187 ± 7, x costs from main analysis: i. Wound infection16,273 ± 18,71219,500 ± 26, ii. Pneumonia14,444 ± 16,12717,356 ± 24, iii. Bed days52,218 ± 47,60460,269 ± 76, Cost estimates if including non- statistically significant complications 13,890 ± 13,59516,303 ± 21,