( BMJ. 2010;341:c5462) ACTRN12609000236291

1. Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting:randomized control trial (BMJ. 2010;341:c5462) ACTRN12609000236291

2. Background • COPD is a major health problem in many countries • The course of the disease is characterised by episodes of acute exacerbation which often require hospitalisation • Standard prehospital management of an acute exacerbation includes nebulised bronchodilators, corticosteroids and oxygen • Oxygen saves lives by preventing hypoxaemia • High flow oxygen in “normal” people leads to an increase in minute ventilation and a decrease in ETCO2 • In COPD hyperoxia leads to a decrease in minute ventilation and an increase in transcutaneous CO2 • Considerable level III/IV evidence that injudicious use of O2 can be harmful lead to BTS guidelines on the emergency use of O2 in adults • Absence of level I/II evidence thought to be contributing to poor uptake

3. Objectives • To compare standard high flow oxygen treatment with titrated oxygen treatment for patients with an acute exacerbation of COPD

4. Methods • Prospective, randomised, controlled, single centre, parallel group trial with 2 arms: • Active • Controlled oxygen therapy to maintain SpO2 between 88-92% using nasal prongs with nebulisation of medication by handheld air driven compressor for the duration of the ambulance transport • Control • High Flow oxygen treatment (8-10 L/min) by non re-breather mask and all nebulised medication driven by 6-8L/min oxygen for the duration of the transport by ambulance • Tasmanian Ambulance Service • Clustered randomisation of paramedics • Computerised random number generation after stratification by rurality (to control for transportation time)

5. Eligibility • Inclusion criteria • ≥ 35 years • Breathlessness and history or risk of COPD • Appropriate acute symptoms • Self reported history of COPD or emphysema or >10 pack year history of smoking • Transport and treatment by Tasmanian ambulance staff • Subgroup with FEV1/FVC ratio ≤ 0.7 • Exclusion criteria • Nil reported but asthma patients listed in trials registry application

6. Randomisation and blinding • Paramedics (not patients) were the unit of randomisation • Cluster randomisation used (to avoid contamination across treatment groups) • Computerised random number generation after stratification by rurality (to control for transportation time) • Randomisation of paramedic responsible for treatment took precedence if multiple attendees • Open label

7. Endpoints • The primary efficacy endpoint was • Superiority in prehospital and in-hospital mortality outcomes • Secondary endpoints included • Incidence of ventilation • Length of hospital stay • Arterial blood gases • pH • CO2 • HCO3- • O2

8. Statistical Analysis • Sample size based on absolute reduction in mortality of 12% • 83% power, α=5%?, reduction from 14% (high flow) 2% (titrated) - plus a margin • N=270 total patients (135:135) • Primary analysis conducted as intention-to-treat and per protocol by log binomial regression to obtain relative risk • Secondary analyses conducted in various populations by (non-paired) Student’s t test following transformation of non-normally distributed data • All analyses assessed using two-sided superiority tests, α=5% (p<0.05 considered significant)

9. Subject disposition

10. Demographics and baseline characteristics

11. Demographics and baseline characteristics

12. Intention to treat analysis

13. Per protocol analysis

14. Results • Titrated O2 reduced mortality compared with high flow O2 by 58% for all patients (RR 0.42, 95%CI 0.20 to 0.89; P=0.02) and by 78% for the patients with confirmed COPD (RR 0.22, 95%CI 0.05 to 0.91; P=0.04) • Patients with COPD who received titrated O2 according to the protocol were significantly less likely to have respiratory acidosis (mean difference in pH 0.12 (SE 0.05); P=0.01; n=28) or hypercapnia (mean difference in arterial carbon dioxide pressure −33.6 (16.3) mm Hg; P=0.02; n=29) than were patients who received high flow O2 • Number needed to harm by using high flow O2=14

15. Results • Titrated O2 reduced mortality compared with high flow O2 by 58% for all patients (RR 0.42, 95%CI 0.20 to 0.89; P=0.02) and by 78% for the patients with confirmed COPD (RR 0.22, 95%CI 0.05 to 0.91; P=0.04) • Patients with COPD who received titrated O2 according to the protocol were significantly less likely to have respiratory acidosis (mean difference in pH 0.12 (SE 0.05); P=0.01; n=28) or hypercapnia (mean difference in arterial carbon dioxide pressure −33.6 (16.3) mm Hg; P=0.02; n=29) than were patients who received high flow O2 • Number needed to harm by using high flow O2=14 (9%-2%=7%; 100/7=14)

16. PICO1 P Patients with COPD I O2 titrated to SpO2 88-92% C High flow O2 O prehospital or in hospital mortality Research question: In patients with COPD does O2 titrated to an SpO2 of between 88 and 92% result in reduced prehospital or in hospital mortality compared with high flow O2?

17. 1a. R- Was the assignment of patients to treatments randomised?

18. 1b. R- Were the groups similar at the start of the trial?

19. 2a. A – Aside from the allocated treatment, were groups treated equally?

20. 2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?

21. 3. M - Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received?

22. How large was the treatment effect?

23. How precise was the estimate of the treatment effect?

24. Will the results help me in caring for my patient? (External validity/Applicability) The questions that you should ask before you decide to apply the results of the study to your patient are: • Is my patient so different to those in the study that the results cannot apply? • Is the treatment feasible in my setting? • Will the potential benefits of treatment outweigh the potential harms of treatment for my patient?

25. Criticisms • No adjustment for or discussion of multiple hypothesis testing • Not blind • Patients not randomised/randomisation process at patient level was manipulated • Study was poorly controlled in terms of other care received • No details provided on clustering • No SpO2 evidence of titration effect • Trial registered after it was completed • The conclusion that patients with COPD who received titrated O2 per protocol were less likely to have respiratory acidosis or hypercapnia than patients who received high flow O2 may be invalid because of multiple hypothesis testing and sampling bias

26. Bottom line The result everyone wanted to see but concern that this study may not truly constitute level II evidence of effect