Mild hypothermia after intravenous thrombolysis in patients with acute stroke a randomised controlled trial

Address for correspondence: Dr. Ranadhir Mitra, Department of Neuroanaesthesiology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi ‐ 110 029, India. E‐mail: ranadhir.mirtra@gmail.com to standard stroke unit care within 6 hours of symptom onset. Hypothermia was induced with a surface‐cooling device and cold saline infusions (core cooling). Active cooling was stopped gradually after 12 hours at <35.5°C. The primary outcome measure was the number of patients with <36°C body temperature for >80% of the 12‐hour cooling period. They included 36 patients with a median of National Institutes of Health Stroke Scale (NIHSS) score of 9, 1 hour after thrombolysis. Fifteen of 18 (83%) patients achieved the primary end point. Sixteen (89%) patients reached <35.5°C in a median time of 10 hours (range, 7‐16 hours) from symptom onset, spent 10.5 hours (1‐17 hours) in hypothermia, and were back to normothermia in 23 hours (15‐29 hours). Adverse events though few were more common in the hypothermia group. At 3 months, 7 patients (39%) in both groups had good outcome (modified Ranking Scale, 0-2), whereas poor outcome (modified Ranking Scale, 4‐6) was twice more common in the normothermia group (44% versus 22%). Based on the rarity of adverse events and better outcome profile at 3 months the authors concluded that mild hypothermia with a surface‐cooling device in an acute stroke unit is safe and feasible in awake patients with stroke.

to standard stroke unit care within 6 hours of symptom onset. Hypothermia was induced with a surface-cooling device and cold saline infusions (core cooling). Active cooling was stopped gradually after 12 hours at <35.5°C. The primary outcome measure was the number of patients with <36°C body temperature for >80% of the 12-hour cooling period. They included 36 patients with a median of National Institutes of Health Stroke Scale (NIHSS) score of 9, 1 hour after thrombolysis. Fifteen of 18 (83%) patients achieved the primary end point. Sixteen (89%) patients reached <35.5°C in a median time of 10 hours (range, 7-16 hours) from symptom onset, spent 10.5 hours (1-17 hours) in hypothermia, and were back to normothermia in 23 hours (15-29 hours). Adverse events though few were more common in the hypothermia group. At 3 months, 7 patients (39%) in both groups had good outcome (modified Ranking Scale, 0-2), whereas poor outcome (modified Ranking Scale, 4-6) was twice more common in the normothermia group (44% versus 22%). Based on the rarity of adverse events and better outcome profile at 3 months the authors concluded that mild hypothermia with a surface-cooling device in an acute stroke unit is safe and feasible in awake patients with stroke.
After arrival of alteplase, concerns regarding the r i s k o f i n t r a c e r e b r a l h a e m o r r h a g e b e c a u s e of hypothermia-induced thrombocytopenia and coagulopathy were addressed by the COOL AID I trial. [5] They recruited 19 patients with NIHSS score of >15) who received alteplase for thrombolysis. Ten patients were subjected to hypothermia (via surface cooling) and nine patients served as controls. Hypothermia was implemented within 6.2 ± 1.3 hours of symptom onset. Cooling to a core temperature of 32°C was achieved in 3.5 ± 1.5 hours. Adverse events were more common in the hypothermia group but mean modified Rankin Scale scores were 3.1 ± 2.3 at 3 months, versus 4.2 ± 1.6 in non hypothermic patients. This trial went on to prove the feasibility and safety of combining thrombolytic therapy and hypothermia in patients with acute ischaemic stroke.
The Intravascular Cooling for the Treatment of Stroke-Longer window (ICTuS-L) [6] further investigated the feasibility and safety of intravenous alteplase combined with intravascular cooling. The trial included 59 patients divided into two cohorts. The first cohort Although hypothermia has been used in multiple clinical settings, it has proven neuroprotective effect in clinical trials of global cerebral ischaemia for cardiac arrest and newborn hypoxic encephalopathy. [1,2] In the era preceding thrombolysis, following the prospective, observational analysis of the Copenhagen Stroke Study Registry that for each 1°C increase in body temperature at admission after acute stroke, the relative risk of poor outcome rose by 2.23. [3] Kammersgaard et al., [4] conducted a feasibility and safety trial of hypothermia for stroke patients. Seventeen patients (cases) with stroke admitted within 12 hours from stoke onset (mean 3.25 hours) were given hypothermic treatment for 6 hours by the "forced air" method (surface cooling) with antishivering medication Pethidine. Cases were compared with 56 matched patients (controls) from the Copenhagen Stroke Study. Mortality at 6 months after stroke was 12% in cases versus 23% in controls. Final neurological impairment (Scandinavian Stroke Scale score at 6 months) was mean 42.4 points in cases versus 47.9 in controls. Authors concluded that induced hypothermia was not associated with poor outcome, death, or an increased incidence of infectious complications with shivering being the most common adverse event. This study went to spawn all further studies investigating hypothermic neuroprotection in acute stroke.
The current study by Piironen et al., a randomised controlled trial from Helsinki University Central Hospital was undertaken to study the safety and feasibility of mild hypothermia in awake patients with stroke who have already received intravenous thrombolysis. Patients were randomised to mild hypothermia (35°C) or Journal of Neuroanaesthesiology and Critical Care | Vol. 1 • Issue 2 • May-Aug 2014 | included patients who presented within 3 hours of symptom onset who received the standard dose of intravenous alteplase, and were then randomised to therapeutic hypothermia or standard medical care. The second cohort of patients presented at 3-6 hours of onset and was randomised to four groups as follows: no treatment, treatment with alteplase only, treatment with hypothermia only or combined therapy. The hypothermia protocol included endovascular cooling for 24 hours and controlled rewarming for 12 hours. Because of technical difficulties, hypothermia was not achieved in two of 28 patients randomised to cooling groups. Although the incidence of pneumonia was higher in the hypothermia groups, there were no statistically significant differences in outcome or death at 3 months among the groups.
There are two other ongoing trials addressing the same issue of therapeutic efficacy of hypothermia. The ICTuS 2/3 study has a projected enrolment of 1600 patients and aims to establish whether the combination of thrombolysis and therapeutic hypothermia (Endovascular catheter cooling to a target temperature of 33°C) is superior to thrombolysis alone in acute ischaemic stroke. The target time for catheter placement is within 2 hours of completion of the intravenous alteplase infusion, followed by cooling for 24 and 12 hours of rewarming. The primary outcome measure of ICTuS 2/3 is favourable outcome defined as a 90-day modified Rankin scale score of 0 or 1, with secondary outcomes of 90-day NIHSS, Barthel Index score, modified Rankin scale score, mortality, incidence of symptomatic intracranial haemorrhage, adverse events and serious adverse events. Hypothermia attenuates neuronal damage in the injured brain by affecting varied pathways activated due to ischaemia. These include energy depletion, ion shifts, free radical formation, EAA release and inflammation. [1] Cerebral oxygen consumption is reduced at a rate of approximately 6% per 1°C decrease in temperature, allowing reduced oxidative debt in times of ischaemia. This, in turn, maintains ionic homeostasis and prevents release of ischaemia-induced excitatory amino acids, free radicals and inflammatory responses which can increase recruitment of ischaemic penumbra.
Hong et al., carried out a prospective cohort study at two stroke centres to investigate the clinical and radiological effects of therapeutic hypothermia in acute ischaemic stroke patients after recanalisation. They enrolled patients with acute ischaemic stroke of the anterior circulation with an initial National Institutes of Health Stroke Scale (NIHSS) ≥10 who had successful recanalisation (i.e., thrombolysis in cerebral ischaemia). Patients at one centre underwent a mild hypothermia (34.5°C) protocol, which included mechanical ventilation, and 48-hour hypothermia and 48-hour rewarming while patients at the other centre were treated according to the guidelines without hypothermia. Cerebral oedema, haemorrhagic transformation, good outcome (3-month modified Rankin Scale, ≤2), mortality and safety profiles were compared. All potential variables were analyzed before and after initiating intervention. The hypothermia group (n = 39) had less cerebral oedema (P = 0.001), haemorrhagic transformation (P = 0.016) and better outcome (P = 0.017) compared with the normothermia group (n = 36). Mortality, haemicraniectomy rate and medical complications were comparable in both