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 .

Population Hyperthermic patients with acute ischemic stroke

Intervention Treatment of hyperthermia

Comparator No treatment

Outcome 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$)).tw.4. 1 or 2 or 35. Fever/6. body temperature/7. (fever$ or hyperthermi$ or pyrexi$).tw.8. (temperature$ adj5 (high$ or rise or raised or elevated or change$ or fluctuat$)).tw.9. 5 or 6 or 7 or 810. Hypothermia, induced/11. cryotherapy/ or body temperature regulation/12. cold temperature/ or ice/ or extreme cold/13. exp antipyretics/ or exp Anti-Inflammatory Agents, Non-Steroidal/ or exp steroids/ or exp adrenal cortex hormones/14. acetaminophen/ or aspirin/ or diflunisal/ or ibuprofen/ or dipyrone/ or diclofenac/ or ketoprofen/ or naproxen/ or flurbiprofen/ or indomethacin/ or tolmetin/ or sulindac/ or etodolac/ or ketorolac/ or piroxicam/ or mefenamic acid/ or meclofenamic acid/ or flufenamic acid/ or prednisolone/ or prednisone/ or cortisone/ or hydrocortisone/ or methylprednisolone/ or dexamethasone/15. (fever$ 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/10-2325. 4 and 9 and 2426. Fever/dt, th [Drug Therapy, Therapy]27. 4 and 2628. 25 or 2729. exp animals/ not humans.sh.30. 28 not 2931. heat stroke/ or heat stroke.tw.32. 30 not 31

PICO1

Potentially relevant papers identified and screened for retrievaln=3501

Studies excluded during initial screeningn=3347

Studies retrieved for more detailed evaluationn=154

Studies excluded during detailed evaluationn=151

Studies included in the meta-analysisn=3

PICO1 – functional outcome

PICO1 – functional outcome

Population Hyperthermic patients with acute ischemic stroke

Intervention Treatment of hyperthermia

Comparator No treatment

Outcome Mortality

PICO1 - mortality

PICO1 - 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.

Population Normothermic patients with acute ischemic stroke

Intervention Prevention of hyperthermia

Comparator No treatment

Outcome 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$)).tw.4. 1 or 2 or 35. fever/pc6. (normothermia or normothermic or afebrile or without fever or no fever).tw.7. ((fever$ 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$).tw.11. 5 or 6 or 7 or 8 or 9 or 1012. Hypothermia, induced/13. cryotherapy/ or body temperature regulation/14. cold temperature/ or ice/ or extreme cold/15. exp antipyretics/ or exp Anti-Inflammatory Agents, Non-Steroidal/ or exp steroids/ or exp adrenal cortex hormones/16. acetaminophen/ or aspirin/ or diflunisal/ or ibuprofen/ or dipyrone/ or diclofenac/ or ketoprofen/ or naproxen/ or flurbiprofen/ or indomethacin/ or tolmetin/ or sulindac/ or etodolac/ or ketorolac/ or piroxicam/ or mefenamic acid/ or meclofenamic acid/ or flufenamic acid/ or prednisolone/ or prednisone/ or cortisone/ or hydrocortisone/ or methylprednisolone/ or dexamethasone/17. (hypothermi$ 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/12-2325. 4 and 11 and 2426. *Fever/pc and 427. 25 or 2628. exp animals/ not humans.sh.29. 27 not 2830. heat stroke/ or heat stroke.tw.31. 29 not 3032. (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).ti33. 31 not 32

PICO2

Potentially relevant papers identified and screened for retrievaln=833

Studies excluded during initial screeningn=820

Studies retrieved for more detailed evaluationn=13

Studies excluded during detailed evaluationn=9

Studies included in the meta-analysisn=4

PICO2 – functional outcome

PICO2 – functional outcome

Population Normothermic patients with acute ischemic stroke

Intervention Prevention of hyperthermia

Comparator No treatment

Outcome Mortality

PICO2

PICO2 - mortality

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.

Population Patients with acute ischemic stroke

Intervention Induction of hypothermia

Comparator No intervention

Outcome 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$)).tw.4. 1 or 2 or 35. Hypothermia, induced/6. cryotherapy/7. cold temperature/ or ice/ or extreme cold/ or shivering/8. (hypothermi$ 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$).tw.13. 11 and 1214. ((cool or cold or ice-cold) adj5 (therap$ 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.18. 5 or 6 or 7 or 8 or 9 or 10 or 13 or 14 or 15 or 16 or 1719. 4 and 1820. exp animals/ not humans.sh.21. 19 not 2022. heat stroke/ or heat stroke.tw.23. 21 not 2224. (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.25. 23 not 24

PICO3

Potentially relevant papers identified and screened for retrievaln=4790

Studies excluded during initial screeningn=4729

Studies retrieved for more detailed evaluationn=61

Studies excluded during detailed evaluationn=55

Studies included in the meta-analysisn=6

PICO3 – functional outcome

PICO3 – functional outcome

Population Patients with acute ischemic stroke

Intervention Induction of hypothermia

Comparator No intervention

Outcome Mortality

PICO3

PICO3 - mortality

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.