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Randomized Controlled Trial
. 2019 May 1;76(5):571-579.
doi: 10.1001/jamaneurol.2018.4822.

Outcomes of Hypothermia in Addition to Decompressive Hemicraniectomy in Treatment of Malignant Middle Cerebral Artery Stroke: A Randomized Clinical Trial

Hermann Neugebauer  1 , Hauke Schneider  2   3 , Julian Bösel  4   5 , Carsten Hobohm  6   7 , Sven Poli  8 , Rainer Kollmar  9   10 , Jan Sobesky  11   12 , Stefan Wolf  13 , Miriam Bauer  14 , Sascha Tittel  15 , Jan Beyersmann  15 , Johannes Woitzik  13 , Peter U Heuschmann  16   17 , Eric Jüttler  1   18
Affiliations
Randomized Controlled Trial

Outcomes of Hypothermia in Addition to Decompressive Hemicraniectomy in Treatment of Malignant Middle Cerebral Artery Stroke: A Randomized Clinical Trial

Hermann Neugebauer et al. JAMA Neurol. .

Erratum in

  • Errors in Multiple Sections.
    [No authors listed] [No authors listed] JAMA Neurol. 2019 May 1;76(5):626. doi: 10.1001/jamaneurol.2019.0131. JAMA Neurol. 2019. PMID: 30801622 Free PMC article. No abstract available.

Abstract

Importance: Moderate hypothermia in addition to early decompressive hemicraniectomy has been suggested to further reduce mortality and improve functional outcome in patients with malignant middle cerebral artery (MCA) stroke.

Objective: To investigate whether moderate hypothermia vs standard treatment after early hemicraniectomy reduces mortality at day 14 in patients with malignant MCA stroke.

Design, setting, and participants: This randomized clinical trial recruited patients from August 2011 through September 2015 at 6 German university hospitals with dedicated neurointensive care units. Of the patients treated with hemicraniectomy and assessed for eligibility, patients were randomly assigned to either standard care or moderate hypothermia. Data analysis was completed from December 2016 to June 2018.

Interventions: Moderate hypothermia (temperature, 33.0 ± 1.0°C) was maintained for at least 72 hours immediately after hemicraniectomy.

Main outcomes and measures: The primary outcome was mortality rate at day 14 compared with the Fisher exact test and expressed as odds ratio (ORs) with 95% CIs. Rates of patients with serious adverse events were estimated for the period of the first 14 days after hemicraniectomy and 12 months of follow-up. Secondary outcome measures included functional outcome at 12 months.

Results: Of the 50 study participants, 24 were assigned to standard care and 26 to moderate hypothermia. Twenty-eight were male (56%); the mean (SD) patient age was 51.3 (6.6) years. Recruitment was suspended for safety concerns: 12 of 26 patients (46%) in the hypothermia group and 7 of 24 patients (29%) receiving standard care had at least 1 serious adverse event within 14 days (OR, 2.05 [95% CI, 0.56-8.00]; P = .26); after 12 months, rates of serious adverse events were 80% (n = 20 of 25) in the hypothermia group and 43% (n = 10 of 23) in the standard care group (hazard ratio, 2.54 [95% CI, 1.29-5.00]; P = .005). The mortality rate at day 14 was 19% (5 of 26 patients) in the hypothermia group and 13% (3 of 24 patients) in the group receiving standard care (OR, 1.65 [95% CI, 0.28-12.01]; P = .70). There was no significant difference regarding functional outcome after 12 months of follow-up.

Interpretation: In patients with malignant MCA stroke, moderate hypothermia early after hemicraniectomy did not improve mortality and functional outcome compared with standard care, but may cause serious harm in this specific setting.

Trial registration: http://www.drks.de, identifier DRKS00000623.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Neugebauer reports having financial affiliations with Boehringer Ingelheim, Bayer, and Daiichi-Sankyo. Dr Bösel reports receiving personal fees from Boehringer Ingelheim, Zoll, Bard, Medtronic, Seiratherm, Sedana Medical, and Thieme and grants from the Patient-Centered Outcomes Research Institute. Dr Kollmar reports having financial affiliations with Boehringer Ingelheim, Bayer, Braincool, and Bard. Dr Heuschmann reports receiving grants from the German Ministry of Research and Education, European Union, Charité–Universitätsmedizin Berlin, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, German Research Foundation, Innovationfond of the Federal Joint Committee, University Göttingen (within the FIND-AF randomized clinical trial; supported by an unrestricted research grant to the University Göttingen from Boehringer Ingelheim), University Hospital Heidelberg (within the Registry of Acute Stroke Under New Oral Anticoagulants–prime randomized clinical trial; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi Sankyo), and Charité–Universitätsmedizin Berlin (within the Mondafis randomized clinical trial; by an unrestricted research grant to the Charité–Universitätsmedizin Berlin from Bayer), outside the submitted work. Dr Jüttler reports reported having financial affiliations with Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Stryker. Dr Poli reports receiving personal fees from CR Bard, outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Flow Diagram
Reasons for exclusion from per-protocol analysis were crossover to the control group in both patients; these 2 patients were allocated to the control group for the as-treated analysis. MCA indicates middle cerebral artery.
Figure 2.
Figure 2.. Temperature and Intracranial Pressure Curves
Body temperatures (A) and intracranial pressure (B) course throughout the first 14 days after randomization. Curves are based on the mean temperature per day in each group; vertical bars indicate SDs. Baseline temperature was normal in both groups at day 1. Hypothermia was induced at day 1. Target temperature was reached in 89% of patients and maintained for a minimum of 72 hours in every patient receiving the assigned treatment. Intracranial pressure curves are based on the mean intracranial measurement per day in each group. Increased intracranial pressure was defined as increase over 20 mm Hg (horizontal line) for a period longer than 10 minutes.
Figure 3.
Figure 3.. Functional Outcome at 12 Months per the Modified Rankin Scale
A secondary end point was functional outcome at 12 months according to the modified Rankin scale. The figure shows the raw distribution of modified Rankin scores at 12 months; of the 23 participants in the control group, 1 (4%) had a score of 2, 6 (26%) had a score of 3, 12 (52%) had a score of 4, 1 (4%) had a score of 5, and 3 (13%) had a score of 6. Of the 25 participants in the hypothermia group, 6 (24%) had a score of 3, 10 (40%) had a score of 4, 3 (12%) had a score of 5, and 6 (24%) had a score of 6.
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