1. CAT Review Therapeutic hypothermia for neuroprotection in adults after cardiopulmonary resuscitation Rosie Macfadyen SpR Intensive Care Unit, Royal Infirmary of Edinburgh

2. Citation Arrich J, Holzer M, Herkner H, Mullner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews 2009, Issue 4 Art no.: CD004128

3. Three part clinical question Patients: – Adult patients who have suffered cardiac arrest – > 18y, in or out of hospital Intervention: – Mild therapeutic hypothermia – <35°C, regardless of method of T° reduction, applied within 6h of arrival at hospital Outcome: – Neurological recovery – best neurologic outcome during hospital stay.

4. The rationale Prevention of postresuscitation syndrome – ↑ CPP – restores energy stores to neurons – But also triggers harmful chemical cascades - ↑ reactive oxygen species, catecholamines, glutamate, dopamine. – BBB disruption – Multifocal damage to brain.

5. The rationale Aims to preserve neurological function in pts comatose post cardiac arrest TH may influence several damaging pathways simultaneously, in addition to ↓ CMRO 2 Inhibition of catecholamine/dopamine/free radical release. Preservation of BBB Preservation of cerebral microcirculation Preservation ATP stores

6. Primary Outcome Neurological recovery – best neurological outcome during hospital stay. Graded as ‘good’ if Cerebral Performance Category 1-2

7. Secondary outcomes – Survival to hospital discharge – Survival at 6 months – Long-term dependency – Cost effectiveness Examination of adverse events

8. Measure of effect Relative risk of achieving good neurological recovery in patients allocated to hypothermia compared to those not receiving hypothermia at hospital discharge

9. Study selection Limited to randomised and ‘quasi-randomised’ trials on adult patients remaining comatose after cardiac arrest. 5 trials met criteria – 481 patients in total – HACA NEJM 2002 ‘the European one’- 275 pts – Bernard NEJM 2002 ‘the Australian one’ – 77 pts – Hachimi-Idrissi Resuscitation 2001 – 33 pts – Laurent J Am Coll Cardiol 2005 – 42 pts – Mori Crit Care Med 2000 - 54

10. Clinical heterogeneity 3/5 trials ‘conventional cooling methods’ Duration of cooling variable; 3-72h Laurent – high-volume haemofiltration 200ml/kg/hr Mori – unclear cooling method These two study analysed separately – effect not pooled with other studies.

11. Risk of Bias Mode of randomization, allocation concealment – 3/5 adequate – HACA, Hachimi-idrissi, Laurent Level of blinding at follow-up – 3/5 adequate – Bernard, HACA, Hachimi-Idrissi Loss to follow-up – HACA – lost 2/275 patients Comparability of groups – HACA – some baseline differences between groups – adjusted for. – Bernard – differences in sex/rate of bystander CPR between groups – not adjusted for – Mori- no information on baseline characteristics of patient groups

12. Neurological outcome: cooling vs no cooling

13. Survival to discharge: cooling vs no cooling

14. Secondary outcomes Survival at 6 months and long-term – No data on this outcome Quality of life and long-term dependency – No data on this outcome Cost effectiveness – No data on this outcome

15. Subgroup analyses Likely to benefit – OOHCA – 4/5 looked only at OOHCA – Presumed cardiac aetiology – VF/VT Unable to ascertain benefit – In hospital cardiac arrest – Asystole as presenting rhythm – Non-cardiac causes of arrest

16. Adverse events No statistically significant differences in events in cooled vs non-cooled – Bleeding – Pneumonia – Sepsis – Pancreatitis – Renal failure/need for RRT – Pulmonary oedema – Seizures – Lethal arrhythmias – Hypocalcaemia/hypophosphataemia

17. 12 EBM Questions Do the methods allow accurate testing of the hypothesis? - Yes Do the statistical tests correctly test the results to allow differentiation of statistically significant results? - Yes Are the calculations valid in the light of the results? -Yes

18. Did any results get omitted and why? – Extracorporeal cooling/unclear cooling methods Did they suggest any other areas of research? – Need further data before supporting therapeutic hypothermia in; in-hospital arrests, asystole, non-cardiac aetiology – Optimal cooling protocol

19. Did they make any recommendations based on the results and were they appropriate? – Conventional cooling post-arrest seems to improve survival. Reviewers findings support current ILCOR guidelines What level of evidence d oes the study represent? 1+/1- What grade of recommendation can I make on this result alone? A Is the study relevant to my clinical practice? Yes

20. What grade of evidence can I make when this study is considered along with other available evidence? A Should I change my practice because of these results? Yes Should I audit my current practice because of these results? Yes

21. Citation ArrichJ, Holzer M, Herkner H, Mullner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews 2009, Issue 4 Art no.: CD004128

22. SHAMELESS PLUG Scottish Intensive Care Society Education Meeting Monday 25 th and Tuesday 26 th October 2010 Royal College of Physicians Edinburgh Approved for 10 CPD points ! http://www.scottishintensivecare.org.uk/meetings/index.htm For programme and application form