Members of the temperature module: T. Dziedzic (Poland), P. Michel (Switzerland), V. Papavasileiou (Greece), J. Petersson (Sweden), D. Staykov (Germany). Chairs of the ESO guidelines committee: J. Mas (France), T. Steiner (Germany). Nice, ESC2014 ESO Guidelines: Temperature management in acute ischaemic stroke George Ntaios MD, MSc (ESO Stroke Medicine), PhD, FESO University of Thessaly, Larissa, Greece

Disclosures Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis. Honoraria: Medtronic; Quintiles; CHUV; Belgian Stroke Council. Speaker fees: Sanofi; Boehringer-Ingelheim. Consultant fees: Boehringer-Ingelheim. Support to attend conferences: Bayer; Sanofi-Aventis; Pfizer; Lundbeck; Boehringer-Ingelheim; Galenica; Elpen; Bristol Myers Squibb. Participation in trials: – ENOS / National coordinator. (Greece) – BPREVISE / Principal investigator. – FOURIER / Sub-investigator. – GLORIA / Sub-investigator.

P opulation Hyperthermic patients with acute ischemic stroke I ntervention Treatment of hyperthermia C omparator No treatment O utcome Functional outcome / Mortality PICO1

1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or exp brain infarction/ or hypoxia-ischemia, brain/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid artery, internal, dissection/ or intracranial arterial diseases/ or cerebral arterial diseases/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or exp "intracranial embolism and thrombosis"/ or exp stroke/ or vertebral artery dissection/ 2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation or basilar artery or vertebral artery) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw or 2 or 3 5. Fever/ 6. body temperature/ 7. (fever$ or hyperthermi$ or pyrexi$).tw. 8. (temperature$ adj5 (high$ or rise or raised or elevated or change$ or fluctuat$)).tw or 6 or 7 or Hypothermia, induced/ 11. cryotherapy/ or body temperature regulation/ 12. cold temperature/ or ice/ or extreme cold/ 13. exp antipyretics/ or exp Anti-Inflammatory Agents, Non-Steroidal/ or exp steroids/ or exp adrenal cortex hormones/ 14. acetaminophen/ or aspirin/ or diflunisal/ or ibuprofen/ or dipyrone/ or diclofenac/ or ketoprofen/ or naproxen/ or flurbiprofen/ or indomethacin/ or tolmetin/ or sulindac/ or etodolac/ or ketorolac/ or piroxicam/ or mefenamic acid/ or meclofenamic acid/ or flufenamic acid/ or prednisolone/ or prednisone/ or cortisone/ or hydrocortisone/ or methylprednisolone/ or dexamethasone/ 15. (fever$ adj3 (control$ or manage$)).tw. 16. (hypothermi$ adj5 (therapeutic or artificial or induced or induction or intentional or therap$ or process or protocol$ or protective or cap or caps or helmet$ or scalp)).tw. 17. (temperature$ adj5 (lower$ or low or decreas$ or reduc$ or normal or control$ or management)).tw. 18. normothermi$.tw. 19. ((cool or cold) adj5 (therap$ or temperature$ or device$ or equipment or fluid or catheter$ or bath$)).tw. 20. (cryother$ or cryogen$ or cryotreat$).tw. 21. (cooling or cooled or chilling or chilled or cools or coolcap or coolant or ice or icepack$ or cold water or iced water or water blanket or sponging or bathing or fan or fanning or coolgard).tw. 22. ((cool or cold) adj5 (blanket$ or collar or helmet or hood)).tw. 23. (antipyretic$ or anti-pyretic$ or antifebril$ or anti-febril$ or antiinflammatory or anti-inflammatory or NSAID$ or steroid$ or corticosteroid$ or glucocorticoid$ or corticoid$ or adrenal cortex hormone$ or acetaminophen or paracetamol or aspirin or acetylsalicylic acid or acetyl salicylic acid or ibuprofen or metamizole or dipyrone or diclofenac or ketoprofen or diflunisal or salsalate or naproxen or fenoproxen or dexketoprofen or flurbiprofen or oxaprozin or loxoprofen or indomethacin or tolmetin or sulindac or etodolac or ketorolac or aceclofenac or piroxicam or meloxicam or tenoxicam or droxicam or lornoxicam or isoxicam or mefenamic acid or meclofenamic acid or flufenamic acid or tolfenamic acid or celecoxib or rofecoxib or valdecoxib or parecoxib or lumiracoxib or etoricoxib or firocoxib or nimesulide or licofelone or prednisolone or prednisone or cortisone or cortisol or hydrocortisone or methylprednisolone or dexamethasone).tw. 24. or/ and 9 and Fever/dt, th [Drug Therapy, Therapy] and or exp animals/ not humans.sh not heat stroke/ or heat stroke.tw not 31

PICO1 Potentially relevant papers identified and screened for retrieval n=3501 Studies excluded during initial screening n=3347 Studies retrieved for more detailed evaluation n=154 Studies excluded during detailed evaluation n=151 Studies included in the meta-analysis n=3

PICO1 – functional outcome

P opulation Hyperthermic patients with acute ischemic stroke I ntervention Treatment of hyperthermia C omparator No treatment O utcome Mortality PICO1 - mortality

PICO1 – Grade Evidence Profile

PICO1 – Recommendations Due to the very low quality of current evidence, no specific recommendation can be made about the usefulness of treatment of hyperthermia to improve functional outcome or decrease mortality in hyperthermic patients with acute ischaemic stroke.

P opulation Normothermic patients with acute ischemic stroke I ntervention Prevention of hyperthermia C omparator No treatment O utcome Functional outcome / Mortality PICO2

1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or exp brain infarction/ or hypoxia-ischemia, brain/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid artery, internal, dissection/ or intracranial arterial diseases/ or cerebral arterial diseases/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or exp "intracranial embolism and thrombosis"/ or exp stroke/ or vertebral artery dissection/ 2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation or basilar artery or vertebral artery) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw or 2 or 3 5. fever/pc 6. (normothermia or normothermic or afebrile or without fever or no fever).tw. 7. ((fever$ or hyperthermi$ or pyrexi$) adj5 (prevent$ or prophylaxis or prophylactic or protect$)).tw. 8. (temperature$ adj5 (high$ or rise or raised or elevated or change$ or fluctuat$) adj5 (prevent$ or prophylaxis or prophylactic or protect$)).tw. 9. ((maintain or maintenance) adj5 (normothermi$ or (normal adj3 temperature))).tw. 10. fever/ and (prevent$ or prophylaxis or prophylactic or protect$).tw or 6 or 7 or 8 or 9 or Hypothermia, induced/ 13. cryotherapy/ or body temperature regulation/ 14. cold temperature/ or ice/ or extreme cold/ 15. exp antipyretics/ or exp Anti-Inflammatory Agents, Non-Steroidal/ or exp steroids/ or exp adrenal cortex hormones/ 16. acetaminophen/ or aspirin/ or diflunisal/ or ibuprofen/ or dipyrone/ or diclofenac/ or ketoprofen/ or naproxen/ or flurbiprofen/ or indomethacin/ or tolmetin/ or sulindac/ or etodolac/ or ketorolac/ or piroxicam/ or mefenamic acid/ or meclofenamic acid/ or flufenamic acid/ or prednisolone/ or prednisone/ or cortisone/ or hydrocortisone/ or methylprednisolone/ or dexamethasone/ 17. (hypothermi$ adj5 (therapeutic or artificial or induced or induction or intentional or therap$ or process or protocol$ or protective or cap or caps or helmet$ or scalp)).tw. 18. (temperature$ adj5 (lower$ or low or decreas$ or reduc$ or control$ or manage$ or monitor$)).tw. 19. ((cool or cold) adj5 (therap$ or temperature$ or device$ or equipment or fluid or catheter$ or bath$)).tw. 20. (cryother$ or cryogen$ or cryotreat$).tw. 21. (cooling or cooled or chilling or chilled or cools or coolcap or coolant or ice or icepack$ or cold water or iced water or water blanket or sponging or bathing or fan or fanning or coolgard).tw. 22. ((cool or cold) adj5 (blanket$ or collar or helmet or hood)).tw. 23. (antipyretic$ or anti-pyretic$ or antifebril$ or anti-febril$ or antiinflammatory or anti-inflammatory or NSAID$ or steroid$ or corticosteroid$ or glucocorticoid$ or corticoid$ or adrenal cortex hormone$ or acetaminophen or paracetamol or aspirin or acetylsalicylic acid or acetyl salicylic acid or ibuprofen or metamizole or dipyrone or diclofenac or ketoprofen or diflunisal or salsalate or naproxen or fenoproxen or dexketoprofen or flurbiprofen or oxaprozin or loxoprofen or indomethacin or tolmetin or sulindac or etodolac or ketorolac or aceclofenac or piroxicam or meloxicam or tenoxicam or droxicam or lornoxicam or isoxicam or mefenamic acid or meclofenamic acid or flufenamic acid or tolfenamic acid or celecoxib or rofecoxib or valdecoxib or parecoxib or lumiracoxib or etoricoxib or firocoxib or nimesulide or licofelone or prednisolone or prednisone or cortisone or cortisol or hydrocortisone or methylprednisolone or dexamethasone).tw. 24. or/ and 11 and *Fever/pc and or exp animals/ not humans.sh not heat stroke/ or heat stroke.tw not (neonat$ or newborn$ or new born or pediatric or paediatric or birth or infant or infants or perinatal or peri-natal or baby or babies or child or children).ti not 32

PICO2 Potentially relevant papers identified and screened for retrieval n=833 Studies excluded during initial screening n=820 Studies retrieved for more detailed evaluation n=13 Studies excluded during detailed evaluation n=9 Studies included in the meta-analysis n=4

PICO2 – functional outcome

P opulation Normothermic patients with acute ischemic stroke I ntervention Prevention of hyperthermia C omparator No treatment O utcome Mortality PICO2

PICO2 - mortality

PICO2 - Grade Evidence Profile

PICO2 – Recommendations We recommend against the prevention of hyperthermia as a means to improve functional outcome in normothermic patients with acute ischaemic stroke. Due to the very low quality of current evidence, no specific recommendation can be made for the usefulness of the prevention of hyperthermia to reduce mortality in normothermic patients with acute ischaemic stroke.

P opulation Patients with acute ischemic stroke I ntervention Induction of hypothermia C omparator No intervention O utcome Functional outcome / Mortality PICO3

1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or exp brain infarction/ or hypoxia-ischemia, brain/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid artery, internal, dissection/ or intracranial arterial diseases/ or cerebral arterial diseases/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or exp "intracranial embolism and thrombosis"/ or exp stroke/ or vertebral artery dissection/ 2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation or basilar artery or vertebral artery) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw or 2 or 3 5. Hypothermia, induced/ 6. cryotherapy/ 7. cold temperature/ or ice/ or extreme cold/ or shivering/ 8. (hypothermi$ adj5 (therapeutic or artificial or induce or induced or induction or intentional or therap$ or process or protocol$ or protective or neuroprotect$ or cap or caps or helmet$ or scalp)).tw. 9. hypothermia/ and (therapeutic or artificial or induce or induced or induction or intentional or therap$ or process or protocol$ or protective or neuroprotect$ or cap or caps or helmet$ or scalp).tw. 10. (temperature$ adj5 (lower$ or decreas$ or reduc$ or drop$)).tw. 11. body temperature/ or temperature/ or skin temperature/ 12. (lower$ or decreas$ or reduc$ or drop$).tw and ((cool or cold or ice-cold) adj5 (therap$ or temperature$ or device$ or equipment or fluid or catheter$ or bath$ or air)).tw. 15. (cryother$ or cryogen$ or cryotreat$ or shiver$).tw. 16. (cooling or cooled or chilling or chilled or cools or coolcap or coolant or ice or icepack$ or cold water or iced water or water blanket or sponging or bathing or fan or fanning or coolgard).tw. 17. ((cool or cold or ice-cold) adj5 (blanket$ or collar or helmet or hood)).tw or 6 or 7 or 8 or 9 or 10 or 13 or 14 or 15 or 16 or and exp animals/ not humans.sh not heat stroke/ or heat stroke.tw not (neonat$ or newborn$ or new born or pediatric or paediatric or birth or infant or infants or perinatal or peri-natal or baby or babies or child or children).ti not 24

PICO3 Potentially relevant papers identified and screened for retrieval n=4790 Studies excluded during initial screening n=4729 Studies retrieved for more detailed evaluation n=61 Studies excluded during detailed evaluation n=55 Studies included in the meta-analysis n=6

PICO3 – functional outcome

P opulation Patients with acute ischemic stroke I ntervention Induction of hypothermia C omparator No intervention O utcome Mortality PICO3

PICO3 - mortality

PICO3 - Grade Evidence Profile

PICO3 – Recommendations Due to the low quality of current evidence, no specific recommendation can be made about the usefulness of induced hypothermia in patients with acute ischaemic stroke.

PICO 1-3 – Recommendations For all the above questions where evidence is insufficient, we encourage the recruitment of patients in randomized controlled trials.