1. Dallas 2015 TFQO: Jasmeet Soar #COI 409 EVREV 1: Jasmeet Soar #COI 409 EVREV 2: Anthony Lagina #COI 357 Taskforce: ALS ALS 889 OXYGEN DOSE DURING CPR IN ADULTS 30 January 2015

2. Dallas 2015 COI Disclosure [relevant to this PICO] Jasmeet Soar #COI 409 Commercial/industry None Potential intellectual conflicts None Anthony Lagina COI# 357 Commercial/industry None Potential intellectual conflicts None

3. Dallas 2015 2010 CoS

4. Dallas 2015 2010 Treatment Recommendation There is insufficient evidence to support or refute the use of a titrated oxygen concentration or constant 21% oxygen (room air) when compared with 100% oxygen during adult cardiac arrest. In the absence of any other data there is no reason to change the current treatment algorithm, which includes use of 100% oxygen during adult cardiac arrest.

5. Dallas 2015 C2015 PICO P - In adults with cardiac arrest in any setting I – does giving a maximal oxygen concentration (100% inspired) C – no supplemental oxygen or a reduced oxygen concentration O - change Survival with favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year (9 - critical outcome), Survival at discharge, 30 days, 60 days, 180 days AND/OR 1 year (7/8 - critical outcome)? ROSC (5 - important)?

6. Dallas 2015 2015 Proposed Treatment Recommendations We suggest the use of the maximal feasible inspired oxygen concentration during CPR (weak recommendation, very low quality evidence). In making this recommendation we have considered the limited available evidence, the need to correct tissue hypoxia during CPR, and see no reason to change the current treatment recommendation, which includes use of 100% inspired oxygen during adult cardiac arrest.

7. Dallas 2015 Inclusion/Exclusion & Articles Found [25 Sep 2014] Inclusions - Adults and children, all languages Exclude - Letters, editorials, comments and case reports, newborn and neonatal studies 1047 papers after excluding duplicates 1026 excluded first pass 20 excluded second pass from reading abstracts 1 non RCT identified

8. Dallas 2015 Risk of Bias in studies StudyYear Total Patients Populatio n Industry Funding Eligibility Criteria Exposure/Outcom e Confounding Follow up Spindelboeck2013145 OHCA non- traumatic, and PaO2 measured No High Low

9. Dallas 2015 Key Study Spindelboeck et al. Resuscitation. 2013 Jun;84(6):770-5. P:145 adults OHCA, single EMS receiving 100% inspired oxygen during CPR I: High PaO 2 during CPR C: Low PaO 2 during CPR O: any ROSC, CPC 1 or 2 at discharge

10. Dallas 2015 Low PaO 2 = 0 – 60 mmHg = 0 – 8 kPa Intermediate PaO 2 = 61 – 300 mmHg = 8.1 – 40 kPa High PaO 2 = > 300 mmHg = > 40 kPa

11. Dallas 2015 Spindelboeck et al. Resuscitation. 2013 Jun;84(6):770-5.

12. Dallas 2015

13. Survival with Favorable neurological/functional outcome at discharge/30 days, [CPC 1 or 2 at discharge or day 28 ]

14. Dallas 2015 Survival with Favorable neurological/functional outcome at discharge/30 days, [CPC 1 or 2 at discharge or day 28 ]

15. Dallas 2015 Intermediate PaO 2 vs. Low PaO 2 11/83 vs. 1/32 RR 4.2 (95% CI 0.57 – 31.52) P = 0.16 High PaO 2 vs. Low PaO 2 7/30 vs. 1/32 RR 7.45 (95% CI 0.98 – 57.15) P = 0.053 High PaO 2 vs. Intermediate PaO 2 7/30 vs. 11/83 RR 1.76 (95% CI 0.75 – 4.12) P = 0.19

16. Dallas 2015 1.Only patients with arterial blood gas during CPR included - 860/1005 excluded as no blood gas – very serious bias 2.Study does not look at inspired oxygen - patient's PaO2 during CPR – very serious indirectness 3.Underpowered - small numbers with endpoints, wide CI – serious imprecision 4.PaO 2 values may be low due to underlying disease, all patients received 100% inspired oxygen via tracheal tube.

17. Dallas 2015 ROSC

18. Dallas 2015 ROSC

19. Dallas 2015 Intermediate PaO 2 vs. Low PaO 2 47/83 vs. 7/32 RR 2.59 (95% CI 1.31 – 5.12) P = 0.006 High PaO 2 vs. Low PaO 2 25/30 vs. 7/32 RR 3.81 (95% CI 1.94 – 7.48) P = 0.0001 High PaO 2 vs. Intermediate PaO 2 25/30 vs. 47/83 RR 1.47 (95% CI 1.15 – 1.88) P = 0.002

20. Dallas 2015 Proposed Consensus on Science There are no adult human studies that directly compare maximal inspired oxygen with any other inspired oxygen concentration. For the critical outcome of survival to hospital discharge with favourable neurological outcome (CPC 1 or 2) we identified very low quality evidence (downgraded for very serious risk of bias and very serious indirectness, and serious imprecision) from 1 observational study [Spindelboeck 2013 770] enrolling 145 OHCA patients who had a PaO 2 measured during CPR that showed no difference between an intermediate PaO 2 and low PaO 2 [11/83 vs. 1/32, RR 4.2 (95 CI 0.57 – 31.52) P = 0.16], or between a high PaO 2 and low PaO 2 [7/30 vs. 1/32 RR 7.45 (95 CI 0.98 – 57.15) P = 0.053].

21. Dallas 2015 For the important outcome of ROSC we identified very low quality evidence (downgraded for very serious risk of bias and very serious indirectness, and serious imprecision) from 1 observational study [Spindelboeck 2013 770] enrolling 145 OHCA patients who had a PaO 2 measured during CPR that showed improved ROSC in those with a higher PaO 2 ; [Intermediate PaO 2 vs. Low PaO 2 47/83 vs. 7/32 RR 2.59 (95% CI 1.31 – 5.12) P = 0.006], [High PaO 2 vs. Low PaO 2 25/30 vs. 7/32 RR 3.81 (95% CI 1.94 – 7.48) P = 0.0001], [High PaO 2 vs. Intermediate PaO 2 25/30 vs. 47/83, RR 1.47 (95% CI 1.15 – 1.88) P=0.002]. Proposed Consensus on Science

22. Dallas 2015 In the single identified study [Spindelboeck 2013 770] all patients had tracheal intubation and received 100% inspired oxygen during CPR. The worse outcomes associated with a low PaO 2 during CPR could be an indication of illness severity. Proposed Consensus on Science

23. Dallas 2015 2015 Proposed Treatment Recommendations We suggest the use of the maximal feasible inspired oxygen concentration during CPR (weak recommendation, very low quality evidence). In making this recommendation we have considered the limited available evidence, the need to correct tissue hypoxia during CPR, and see no reason to change the current treatment recommendation, which includes use of 100% inspired oxygen during adult cardiac arrest.

24. Dallas 2015 Knowledge Gaps We do not know the optimal arterial or tissue oxygen targets during CPR. We do not have any way of reliably monitoring oxygen targets during CPR. We do not know the feasibility of controlling inspired oxygen concentration during CPR. Prospective clinical trials may be warranted to explore different inspired oxygen concentrations (including air) during CPR. The role and feasibility of alternatives to oxygen/air mixtures during CPR.

25. Dallas 2015 Next Steps This slide will be completed during Task Force Discussion (not EvRev) and should include: Consideration of interim statement Person responsible Due date