Original research article European Stroke Journal Therapeutic hypothermia for acute 2019, Vol. 4(3) 254–262 ! European Stroke Organisation ischaemic stroke. Results of a European 2019 multicentre, randomised, phase III Article reuse guidelines: sagepub.com/journals-permissions clinical trial DOI: 10.1177/2396987319844690 journals.sagepub.com/home/eso H Bart van der Worp1, Malcolm R Macleod2, Philip MW Bath3, Raj Bathula4, Hanne Christensen5, Bridget Colam2, Charlotte Cordonnier6, Jacques Demotes-Mainard7, Isabelle Durand-Zaleski8, Christian Gluud9, Janus Christian Jakobsen9,10, Bernd Kallmünzer11, Rainer Kollmar12, Derk W Krieger13, Kennedy R Lees14, Dominik Michalski15, Carlos Molina16, Joan Montaner17, Risto O Roine18, Jesper Petersson19, Richard Perry20, Nikola Sprigg3, Dimitre Staykov11,21, Istvan Szabo22, Geert Vanhooren23, Joanna M Wardlaw24, Per Winkel9, Stefan Schwab11 and the EuroHYP-1 investigators Abstract Introduction: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. Patients and methods: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0–35.0 C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. Results: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. 14 School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, UK 1 15 Department of Neurology and Neurosurgery, Brain Center, University Department of Neurology, University of Leipzig, Leipzig, Germany Medical Center Utrecht, Utrecht, The Netherlands 16 Hospital Universitari Vall dHebron, Barcelona, Spain 2 17 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Scotland, UK Barcelona, Spain 3 18 Stroke Trials Unit, Division of Clinical Neuroscience, University of Division of Clinical Neurosciences, Turku University Hospital and Nottingham, Nottingham, UK University of Turku, Turku, Finland 4 19 Stroke Department, Northwick Park Hospital, London, UK Department of Neurology, Skane University Hospital, Malm€ o, Sweden 5 20 Department of Neurology, Bispebjerg og Frederiksberg Hospitaler, Stroke Service, National Hospital for Neurology & Neurosurgery, University of Copenhagen, Copenhagen, Denmark Queen Square, London, UK 6 21 University of Lille, Inserm U1171, Degenerative and Vascular Cognitive Department of Neurology, Hospital of the Brothers of St. John, Disorders, Centre Hospitalier Universitaire Lille, Lille, France Eisenstadt, Austria 7 22 ECRIN, Paris, France European Stroke Research Network for Hypothermia, 8 APHP URCEco, University Paris Est Creteil & INSERM UMR 1123, Brussels, Belgium 23 Paris, France AZ Sint-Jan Brugge-Oostende, Brugge, Belgium AV 9 24 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Edinburgh Imaging, Centre for Clinical Brain Sciences and UK Dementia Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Research Institute, University of Edinburgh, Edinburgh, UK 10 Department of Cardiology, Holbæk Hospital, Copenhagen, Denmark 11 Department of Neurology, University Medical Centre Erlangen, Corresponding author: Erlangen, Germany H Bart van der Worp, Department of Neurology and Neurosurgery, 12 Klinik für Neurologie und Neurointensivmedizin, Klinikum Darmstadt, Brain Center, University Medical Center Utrecht, Heidelberglaan 100, Darmstadt, Germany 3584 CX Utrecht, The Netherlands. 13 Mediclinic Middle East, Dubai, UAE Email: h.b.vanderworp@umcutrecht.nl van der Worp et al. 255 Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48–2.13; p ¼ 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65–1.94; p ¼ 0.52). Discussion: In this trial, cooling to a target of 34.0–35.0 C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. Conclusion: Before new trials are launched, the feasibility of cooling needs to be improved. Keywords Ischaemic stroke, randomised trial, treatment, hypothermia, cooling Date received: 30 November 2018; accepted: 27 February 2019 Introduction between 34.0 C and 35.0 C, started within 6 h of symp- tom onset and maintained for 12 or 24 h, improves In selected patients with acute ischaemic stroke, intra- functional outcome at three months in awake patients venous thrombolysis and endovascular treatment with acute ischaemic stroke. improve functional outcome.1–3 However, among patients treated with thrombolysis within 3 hours of stroke onset in clinical trials, 59% were dead or depen- Methods dent at the end of follow-up,1 and in trials of endovas- cular treatment, 29–67% of the patients randomised to Study design the intervention arm were dead or dependent at three EuroHYP-1 was an investigator-initiated, internation- months.3 In addition, only a minority of patients with al, multicentre, randomised, open-label, blinded acute ischaemic stroke are eligible for revascularisation outcome (PROBE), parallel-group, clinical superiority therapies: the Action Plan for Stroke in Europe 2018– trial, registered at ClinicalTrials.gov as NCT01833312. 2030 aims to achieve rates above 15% for intravenous The trial was coordinated at the University Hospital thrombolysis and above 5% for endovascular therapy Erlangen and funded by the European Union’s (EU) across Europe.4 For this reason, there is an urgent need Seventh Framework Programme under grant agree- for additional treatment strategies that can be applied ment n 278709. The final full study protocol is avail- in a broad range of patients. able as an online supplement to this paper; a summary Therapeutic hypothermia appears a promising can- of the original study protocol and the final statistical didate treatment. Systematic review and meta-analysis plan have been published.12,13 The trial was overseen of animal studies modelling ischaemic stroke have by a steering committee and by an independent data shown convincingly that therapeutic hypothermia and safety monitoring board. Coordination of other reduces infarct size and improves neurological out- trial activities such as training, monitoring, data man- comes. The benefit of hypothermia appears inversely agement, and data analysis were divided over eight related to the temperature achieved, with a reduction institutions in seven European cities. in infarct size of about one third with cooling to 35 C Participants could be enrolled by investigators from and by around 45% with cooling to 34 C.5 Most phase 36 hospital sites in nine countries: Belgium, Denmark, II clinical trials have reported that cooling awake Finland, France, Germany, Italy, Lithuania, Spain and patients with ischaemic stroke to target temperatures the UK. Investigators were certified by web-based of 33–35 C for 12–24 h is feasible and safe, despite an training modules on cooling procedures; training pro- increased risk of pneumonia in some studies.6–10 Both vided by manufacturers of cooling systems on their safety and feasibility were confirmed in a recent phase devices; web-based certification on assessment of the III clinical trial that was terminated prematurely after National Institutes of Health Stroke Scale (NIHSS)14 inclusion of 120 of the intended 1600 patients.11 All and modified Rankin Scale (mRS)15 and provision of published trials were underpowered to detect any written instructions on trial-specific procedures. effect of hypothermia on functional outcome. Experience with therapeutic hypothermia in awake In this randomised clinical trial, we aimed to assess patients with acute stroke was not a requirement. whether systemic cooling to a target body temperature Ethics approval was obtained in each country and 256 European Stroke Journal 4(3) (where required) at each site before the start of the In patients randomised to hypothermia, cooling was study in that country or site. Patients or their represen- started within 6 h after onset of symptoms and within tatives provided written informed consent according to 90 min of start of thrombolysis (or within 90 min of national and local regulations. hospital admission in patients who were not treated with thrombolysis) with intravenous infusion of Patients 20 mL/kg refrigerated normal saline (4 C) over 30– 60 mins or a pre-specified surface cooling method, Patients were eligible if they had a diagnosis of acute depending on local practice and preference. As men- ischaemic stroke; an age of 18 years or older; a score on tioned above, the maximum delay to start of treatment the NIHSS of 6–18 inclusive; a score on the motor after intravenous thrombolysis or study site admission response sub-scale of the Glasgow Coma Scale of 5 was increased to 150 min after the first 50 patients. or 6; a pre-stroke score on the mRS  2; an estimated Cooling was maintained at 34.0–35.0 C for 24 h with body weight of 50–120 kg; a possibility to start thera- a surface or endovascular technique. The choice of the peutic hypothermia within 6 h after onset of stroke; and cooling technique was at the discretion of the local a possibility to start therapeutic hypothermia within investigator, as long as protocol-specified devices 90 min after start of alteplase administration in patients were used. Thereafter, patients were passively receiving thrombolysis or a possibility to start thera- rewarmed at a rate of 0.2  0.1 C per hour until the peutic hypothermia within 90 min after admission to rectal or bladder temperature reached 36.0 C, after the trial site if not receiving thrombolysis. All patients which the cooling device was disconnected. To increase underwent CT or MRI brain imaging to exclude hae- the feasibility of cooling and thereby to increase morrhage and other non-ischaemic causes of stroke; recruitment, the duration of active cooling was reduced the presence of early acute ischaemic signs (e.g. subtle from 24 to 12 hours after inclusion of the first brain hypoattenuation, hyperattenuated artery), prior 50 patients. infarcts, leukoaraiosis or brain atrophy were not exclu- In patients randomised to hypothermia, shivering sion criteria as long as the acute changes were consis- and discomfort were prevented and treated with intra- tent with the known time of symptom onset. An venous pethidine (max 500 mg/24 h) and oral buspirone overview of the reasons for exclusion from the trial is (max 30 mg/24 h). Patients who had difficulties swal- available in the full study protocol. lowing did not receive buspirone unless they had a In an attempt to enhance recruitment after inclusion nasogastric tube. For the prevention of opioid- of the first 50 patients, and to accommodate the wide- induced nausea and vomiting, ondansetron or granise- spread use of endovascular treatment, the upper limit tron were recommended. on the NIHSS was dropped and the time window to All patients were treated according to published start of treatment was increased to 150 min after start guidelines for the treatment of acute ischaemic stroke of alteplase administration in patients receiving throm- and for secondary prevention. bolysis at the trial site, to 150 min after start of endo- vascular treatment, if this was later, and to 150 min Outcomes after admission to the trial site in patients not receiving thrombolysis or in patients who had received throm- The primary outcome was the score on the mRS at 91 bolysis at a different site, without a change in the max- days (14 days), as analysed with ordinal logistic imum time to start of hypothermia of six hours after regression and expressed as a common odds ratio (OR). Secondary outcome included death or dependen- symptom onset. cy, defined as a score on the mRS > 2; death; score on NIHSS; brain infarct size (on CT or MRI, volume, Treatment centrally and blindly assessed); World Health Patients were allocated to hypothermia plus standard Organization Disability Assessment Schedule care or to standard care alone. Randomisation was (WHODAS) 2.0 score and EuroQoL-5D-5L score,16–18 performed through a web-based allocation service all at 91 days, except for brain infarct size that was and involved stratification by country and minimisa- assessed at 48 h. The primary safety variable was the tion on: intention to give alteplase; intended method occurrence of serious adverse events (SAEs) until of cooling (surface or endovascular); sex; stroke sever- day 91. ity (dichotomised between NIHSS 12 and 13); age To allow blinded assessment of the primary outcome (65 years or >65 years); visibility of a relevant ischae- and to enhance statistical power, the mRS at 91 days mic lesion on the first brain imaging (yes or no) and was assessed by at least four independent adjudicators time since symptom onset (4 h or 4–6 h). based on a video recording of the mRS interview, with van der Worp et al. 257 masking to treatment allocation, and coordinated from the University of Glasgow.19 Sample size We originally estimated that a total of 1474 patients was required to detect an absolute reduction in the risk of death or disability (mRS > 2) of 7% (corre- sponding to an OR of 074) with 90% power at the 5% significance level (two sided) and allowing for 3% Figure 1. Flow of patients through the study. loss to follow-up. This target sample size was rounded to 1500 patients. When recruitment proved to be much slower than expected, we aimed for 80% power, allow- hypothermia group and three in the control group ing a reduction in the target sample size to 750 patients, were lost to follow-up at 91 days. which were rounded to 800. Of the 49 patients randomised to hypothermia, 38 (77%) were cooled with surface cooling and 11 with an Statistical analysis endovascular technique. Twenty five patients (51%) had a planned duration of active cooling of 24 h, and Primary and secondary efficacy outcomes were assessed in the intention-to-treat population (all included 24 (49%) of 12 h. Only 15 (31%) of the 49 patients patients). The primary efficacy variable, the score on randomised to hypothermia achieved cooling to the the mRS at 91 days, was intended to be determined extent defined in the study protocol and had a body with ordinal logistic regression. However, because the temperature 35.0 C for at least 6 h during the active proportional odds assumptions of the ordinal regres- cooling period. On the first day after randomisation, sion analyses were not fulfilled in any of the analyses of 18 (37%) patients randomised to hypothermia and the primary outcome, the two groups were also com- 12 (24%) controls were treated on an intensive care pared using van Elteren’s test stratified by nationality, unit or intermediate care unit/high dependency unit. as defined in the statistical analysis plan.13 The other patients were treated on a stroke unit or For secondary and exploratory outcomes frequen- normal ward. cies and percentages per group as well as risk ratios Body temperatures in the first 12 h after randomisa- with 95% confidence intervals (CIs) were reported for tion are shown in Figure 2. binary outcomes. We used logistic regression for binary quantities, the general linear univariate model for con- tinuous outcomes and the Poisson distribution or neg- Efficacy outcomes ative binomial distribution for rate outcomes. If the assumptions of the Poisson or negative binomial In the intention-to-treat analysis, there was no differ- models were not fulfilled with reasonable approxima- ence between the groups in the scores on the mRS at 91 tion, a non-parametric method (van Elteren adjusted days (OR for good outcome, 1.01; 95% CI, 0.48–2.13; by nationality of centre) would be used. p ¼ 0.97; Figure 3). The same applied to the per- Predefined per-protocol analyses were performed in protocol analysis, including 15 patients randomised to all patients who had a body temperature 35.0 C for hypothermia and 46 to standard treatment (OR, 1.07; at least 6 hours during the active cooling period. 95% CI, 0.35–3.32; p ¼ 0.91). There were also no differ- ences in the risks of death or death or dependency at 91 days, the scores on the NIHSS or Visual Analogue Results Scale (VAS) of the EQ-5D-5 L at 91 days, or infarct Enrolment into the trial started in November 2013 and volume at 48 h (Table 2). Per-protocol analyses yielded was stopped in March 2018 after inclusion of 98 essentially the same results as the intention-to-treat patients at 23 study sites because of slow recruitment analyses (data not shown). and the expiration of the funding period. Forty-nine patients were randomly assigned to the hypothermia group and 49 to the control group (Figure 1). At base- Safety outcomes line, the mean age of the patients was 70 years (range, 34–92) and the median score on the NIHSS 11 (inter- Seventeen patients (38%) in the hypothermia group quartile range (IQR), 7–17). Forty three (44%) were and 14 controls (29%) had at least one serious adverse female. Baseline characteristics were balanced between event (relative risk, 1.22; 95% CI, 0.65–1.94; p ¼ 0.52; the two groups (Table 1). One patient in the Table 3). 258 European Stroke Journal 4(3) Table 1. Characteristics of patients at baseline. Intervention Control Characteristic n ¼ 49 n ¼ 49 Age–years mean (SD) 69.6 (11.8) 71.1 (12.0) Male sex – no (%) 28 (57.1) 27 (55.1) Body weight–kg mean (SD) 80 (14.2) 78.9 (13.4) Height–m mean (SD) 170 (10.2) 169 (9.7) NIHSS score–median (IQR) 11 (7–17) 11 (8–17) Location of stroke in 17 (35) 19 (39) left hemisphere – no (%) Pre-stroke mRS score– 0 (0–0) 0 (0–1) median (IQR) Visible acute ischaemic 22 (44.9) 22 (44.9) lesion on CT – no (%) Figure 2. Body temperatures in the first 12 h after start of Systolic blood 154 (26) 153 (23) treatment in the overall trial population. pressure–mm Hg Diastolic blood 84 (18) 85 (14) pressure–mm Hg Body temperature –  C 36.2 (0.49) 36.3 (0.48) mean (SD) Treatment with i.v. 39 (79.6) 41 (83.7) alteplase – no (%) Time from stroke onset 203 (155–244) 220 (164–293) to randomisation – min mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; IQR, interquartile range. Figure 3. Distribution of scores on the modified Rankin Scale at 91 days. regulatory and reporting requirements and the overall degree of complexity had more in common with Discussion industry-initiated trials than with academic-led so- The results of this trial provide no evidence that active called ‘pragmatic’ trials. This further increased the cooling to a target of 34.0–35.0 C for 12–24 h started burden to local investigators. Earlier phase II trials of within 6 h after onset of ischaemic stroke has an impact hypothermia for patients with acute ischaemic stroke in on functional outcome at three months. However, with centres without previous experience with cooling 98 patients included against an original target of 1500, have suggested that much higher recruitment rates the trial was substantially underpowered to detect any are possible with more pragmatic trial designs.9,10 clinically relevant benefit or harm. In addition, only Third, we had chosen to distribute core trial activities one third of the patients randomised to hypothermia across a range of universities and enterprises across reached the predefined cooling targets, which further Europe – on the view that such distribution was more limits the interpretation of the findings. likely to lead to funding success – rather than a more We were disappointed by the small number of conventional centralised approach based in the institu- patients included into the trial despite a project dura- tion of the study sponsor. In retrospect this was an tion of six years, involvement of 36 trial sites and gen- error, and impeded effective trial coordination. We erous funding. We think this may be explained by suggest that future EU-funded trials should have cen- several factors. First, cooling awake patients with tral provision of core trial functions unless the appli- ischaemic stroke is a complex intervention with which cants can provide a compelling reason why this should most study sites had no experience. While centres rec- not be the case. Finally, initiation of study sites was ognised the importance of the scientific question, there severely delayed due to very high and inconsistent was some understandable caution in proceeding from bureaucratic hurdles across Europe and the trial trial approval to recruitment. Regardless of training being variously considered a device trial, a drug trial, and experience, inclusion of an eligible patient into both, or neither in different jurisdictions, each operat- the trial required a major investment in time of study ing under the same EU Clinical Trials Directive. staff during the full treatment period of 12 or 24 h, and Previous small randomised trials had suggested that this was often not feasible. Next, the trial design, cooling to targets ranging from 33 C to 35 C was van der Worp et al. 259 Table 2. Secondary efficacy outcomes. Intervention Control Outcome n ¼ 48 n ¼ 46 RR (95% CI) p Death – n (%) 5 (10.2) 4 (8.2) 1.25 (0.34–3.81) 0.73 Death or dependency – n (%) 24 (50.0) 28 (60.9) 0.82 (0.50–1.14) 0.29 NIHSS – median (IQR) 3 (1–11) 3 (1–8) – 0.39 EQ-5D-5L VAS – median (IQR) 70 (50–90) 67 (50–80) – 0.45 WHODAS 2.0 – median (IQR) 53.5 (5.8–86.5) 38.0 (12.0–74.0) – 0.11 Infarct volume/mL mean (95% CI) 37.5 (13.0–102.8) 34.3 (10.5–65.5) – 0.55 All outcomes are at 91 days, except for infarct volume, which is at 48 h. RR: risk ratio; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; IQR: interquartile range; EQ-5D-5L VAS: Visual Analogue Scale of the EuroQoL 5 dimensions 5 level questionnaire; WHODAS: World Health Organization Disability Assessment Schedule. Scores on the EQ- 5D-5L VAS and WHODAS 2.0 range from 0 to 100, with lower scores indicating poorer outcomes for the VAS, and better outcomes for WHODAS 2.0. Shivering occurred in all our cooled patients and Table 3. Serious adverse events. has been reported as a common adverse effect in all Hypothermia Control previous cooling trials involving awake patients with Event n ¼ 49 n ¼ 49 acute ischaemic stroke, despite anti-shivering regimes. Symptomatic intracranial haemorrhage 4 2 Shivering could be the most important reason for not Space-occupying oedema formation 4 1 reaching and maintaining target temperatures. In our Pneumonia 9 2 study, the dose of pethidine as the main anti-shivering Other infection 4 1 drug was limited to a maximum of 500 mg during the Other serious adverse eventsa 11 10 period of cooling, which is about half that adminis- a Other serious adverse events (n) included seizures (1); TIA (1); myo- tered in previous trials targeting a body temperature cardial infarction (1); impaired wound healing (2); haematuria (1); urinary of 33 C for 24 h8,11 and also substantially less than retention (1); carotid endarterectomy (1); B-cell lymphoma (1); ileus (1) that used in a trial testing surface cooling from 34.0 and pulmonary oedema (1) for hypothermia and TIA (1); cardiomyopathy to 35.0 C.10 The maximum pethidine dose of 500 mg (1); atrial flutter (1); aneurysm formation (1); carotid endarterectomy (1); in our trial was motivated by the maximum daily dose bladder carcinoma (1); renal impairment (1); intoxication (1) and death of unknown cause (2) for control. TIA: transient ischaemic attack. in the drug’s summary of product characteristics (SPC), to which other trials were apparently not feasible in the large majority of patients with acute bound. The pethidine dose in our trial was however ischaemic stroke.6–11 However, these studies were per- higher than the dose of 23 mg/kg used in a recent formed in a few centres, often with experience with surface cooling trial targeting a body temperature of hypothermia, whereas our phase III trial included 35 C for 12 h.9 In that trial, pethidine was combined patients in a total of 23 study sites of which just a with intravenous dexmedetomidine, which we did not few had previous experience with cooling awake use because the SPC of dexmedetomidine reports patients with ischaemic stroke. Before being opened acute cerebrovascular conditions as a contraindication for recruitment, the staff at each study site were not to its use. We think that any new study on hypother- only trained in the study protocol, but also in the tech- mia in patients with acute ischaemic stroke should nique of cooling. Unfortunately, our study showed that only commence after the development and validation it was not possible to achieve cooling targets in the of better methods to prevent shivering majority of non-sedated stroke patients, at the current and discomfort. time with typical limited staffing and equipment resour- In our trial, cooling was associated with an increased ces that are available even in expert centres. One small risk of pneumonia. This is in line with most previous phase II trial in patients with ischaemic stroke has sug- studies of hypothermia in patients with acute ischaemic gested that surface cooling is feasible to 35.0 C, but not stroke, and with findings of a systematic review on to 34.5 C or 34.0 C.10 Future trials of hypothermia in infections in patients treated with hypothermia for awake patients with acute ischaemic stroke could there- any indication.20 In patients with acute stroke, the fore target a modest temperature reduction to 35.0 C occurrence of pneumonia has been associated with a within the usual care environment. Larger reductions in greater risk of a poor outcome.21 It is however uncer- temperature probably require not only more investiga- tain whether pneumonia can be prevented with prophy- tor experience, but also intensive nursing care on an lactic treatment with an antibiotic, and whether this intensive care unit or high-dependency unit. might have an impact on outcome.22 260 European Stroke Journal 4(3) In addition to evidence from animal studies that Declaration of Conflicting Interests cooling improves functional and pathological out- The author(s) declared the following potential conflicts of comes in acute ischaemic stroke,23 the concept of our interest with respect to the research, authorship, and/or pub- trial was supported by randomised trials in adult lication of this article: HBvdW has received speaker’s fees and patients with cardiac arrest in the previous two deca- serves as a consultant to Boehringer Ingelheim; PMB has des, demonstrating benefit of hypothermia.24 However, received honoraria for advisory work from DiaMedica, in a more recent randomised trial in this patient popu- Moleac, Nestle, Phagenesis, Sanofi and ReNeuron; HC has lation, cooling to a target of 33 C did not confer a received speaker’s fees from MSD, Bayer and Medtronic and benefit as compared with maintaining body tempera- served as a consultant to Boehringer Ingelheim. IDZ has ture at 36 C.25 This suggests that in patients with car- diac arrest outcomes may be improved by either received speaker’s fees and/or has served as a consultant to cooling to 36 C, or by the prevention of sub-febrile Bayer Pharma, BMS Pfizer, Boehringer Ingelheim, temperatures and fever. In patients with acute stroke, Medtronic and Sanofi. BK has received speaker’s fees from elevated body temperatures have been associated with Zoll Medical, Medtronic, Boehringer Ingelheim, Daiichi an increased risk of a poor outcome23,26,27 and system- Sankyo and Pfizer. RK has received speaker’s fees from atic review and meta-analysis of animal studies model- Boehringer Ingelheim, Bayer, Bard Medical and Pfizer and ling ischaemic stroke have suggested that this relation serves as consultant to Bard Medical. KRL has received hon- may in part be causal.28 Rather than active cooling, the oraria from Boehringer Ingelheim for participation in prevention of fever could therefore be a target to Independent Data Monitoring Committees; JP has received improve outcomes after stroke. A randomised trial on speaker’s fees and/or has served as a consultant to Biogen, prevention of infections and fever in patients with mod- Braincool, MSD and QuickCool. ROR has received speaker’s erately severe to severe stroke is ongoing.29 fees and/or has served as a consultant to Bayer Pharma, BMS Hypothermia is considered a powerful neuroprotec- Pfizer, Boehringer Ingelheim, Orion Pharma, Biogen, Merck, tive intervention in animal models of stroke, to the Medtronic, Gore, Cardialysis and BrainCool; DS has extent that inadvertent cooling was held to confound received speaker’s fees from Boehringer Ingelheim, Bayer, early laboratory studies. It might be argued that a fail- Daiichi Sankyo, Zoll Medical, Bard Medical, Pfizer and ure of hypothermia to provide neuroprotection in serves as consultant to Zoll Medical and Boehringer human stroke is further evidence that animal studies Ingelheim. ISZ serves Becton Dickinson in a senior manage- do not model human pathophysiology with sufficient ment role as of June 2017. The other authors report no con- fidelity to be a useful guide to developing new treat- flicts of interest. Bard Medical and Zoll Medical have ments. However, differences in thermal mass mean that supported the EuroHYP-1 trial through the provision of tem- the process of cooling a rodent brain can proceed much perature management systems at a preferential prize and more rapidly and with greater control than can be through training of local study staff; Vacutest Kima has achieved in the awake human brain in a busy ward, donated the EuroHYP-1 with materials for blood sampling. and very few patients indeed achieved cooling to target, so we do not believe that our findings have any relevance to the question of the usefulness of Funding animal models. Future studies might explore the effect of more direct approaches to cooling, for The author(s) disclosed receipt of the following financial sup- instance through the instillation of cooled fluids direct- port for the research, authorship, and/or publication of this ly to the cerebral circulation during endovascu- article: The research leading to these results has received lar procedures. funding from the European Union’s Seventh Framework In conclusion, the limited feasibility of the interven- Programme (FP7/2007–2013) under grant agreement n tion under study at the current time and practical hur- 278709. HBvdW was supported by the Dutch Heart dles preventing sufficient recruitment into our trial Foundation (2010T075); PMB is Stroke Association have prevented final conclusions on the benefit of Professor of Stroke Medicine and is a National Institute of hypothermia in awake patients with acute ischaemic Health Research Senior Investigator. The prefunding phase stroke to be made. Improvement of the feasibility of was supported by an unconditional grant from W. Hacke hypothermia in awake stroke patients and simplifica- from his 2009 Max Jarecki and Mihara awards. tion of the study design are required before this treat- ment can be tested again in a randomised trial. For now, the low feasibility that we encountered militates Ethical approval against the premise of our study: with the current meth- Ethics approval was obtained in each country and (where ods, hypothermia is unlikely to be a widely applicable required) at each site before the start of the study in that treatment for patients with acute ischaemic stroke. country or site. van der Worp et al. 261 Informed consent 2. Emberson J, Lees KR, Lyden P, et al. Effect of Patients or their representatives provided written informed treatment delay, age, and stroke severity on the effects consent according to national and local regulations. of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; Guarantor 384: 1929–1935. HBvdW 3. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic Contributorship stroke: a meta-analysis of individual patient data from HBvdW, MRM, PMB, CG, RK, DWK, KRL, JP, IS, JMW five randomised trials. Lancet 2016; 387: 1723–1731. and SS conceived the study and developed the protocol. All 4. Norrving B, Barrick J, Davalos A, et al. Action plan for authors contributed to the conduct of the study, with the stroke in Europe 2018–2030. Eur Stroke J 2018; 3: exception of CG, JCJ and PW who performed the blinded 309–336. statistical analyses. HBvdW wrote the first draft of the man- 5. Van der Worp HB, Sena ES, Donnan GA, et al. uscript. All authors reviewed and edited the manuscript and Hypothermia in animal models of acute ischaemic approved the final version. stroke: a systematic review and meta-analysis. Brain 2007; 130: 3063–3074. Acknowledgements 6. Krieger DW, De Georgia MA, Abou-Chebl A, et al. Cooling for acute ischemic brain damage (cool aid): an Members of the EuroHYP-1 trial who included patients are open pilot study of induced hypothermia in acute ische- (local principal investigator; number of patients included): Universit€atsklinikum Erlangen, Erlangen, DE (S. Schwab; mic stroke. Stroke 2001; 32: 1847–1854. 7. De Georgia MA, Krieger DW, Abou-Chebl A, et al. 13); Department of Neurology, University of Leipzig, Cooling for acute ischemic brain damage (COOL AID): Leipzig, DE (D. Michalski, C. Hobohm; 6); Universit€atsklinikum Carl Gustav Carus, Dresden, DE (H. a feasibility trial of endovascular cooling. Neurology Schneider; 1); Martin-Luther-Universit€at Halle-Wittenberg, 2004; 63: 312–317. 8. Hemmen TM, Raman R, Guluma KZ, et al. Intravenous Halle, DE (K. Wartenberg; 3); Klinikum Altenburger Land, thrombolysis plus hypothermia for acute treatment of Altenburg, DE (J. Berrouschot; 1); Universit€ atsklinikum Frankfurt, Frankfurt, DE (M. Lorenz 3); Bispebjerg ischemic stroke (ICTuS-L): final results. Stroke 2010; Hospital, Copenhagen, DK (H.C. Christensen; 7); 41: 2265–2270. 9. Piironen K, Tiainen M, Mustanoja S, et al. Mild hypo- University of Nottingham, Nottingham, UK (N. Sprigg; 7); Northwick Park Hospital, Northwick, UK (R. Bathula; 10); thermia after intravenous thrombolysis in patients with Royal Liverpool, Liverpool, UK (P. Fitzsimmons; 1); acute stroke: a randomized controlled trial. Stroke 2014; University College London Hospital, London, UK (R. 45: 486–491. Perry; 8); Royal London Hospital, London, UK (K. 10. Geurts M, Petersson J, Brizzi M, et al. 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