Introduction

In patients with acute ischaemic stroke, recanalization of the occluded cerebral artery is strongly associated with improved functional outcome [1]. Spontaneous recanalization is influenced by temperature-dependent enzymes [2], and the in vitro activity of alteplase reduces with lower temperatures [3]. Whether body temperature also affects in vivo recanalization with or without alteplase is uncertain. This might be important, because guidelines recommend the use of antipyretics in stroke patients with fever [4, 5] and two phase III trials of therapeutic hypothermia for ischaemic stroke are in progress [6, 7]. We assessed the relation between body temperature and recanalization in patients with acute ischaemic stroke, treated with or without intravenous alteplase.

Methods

This is a substudy of the Dutch acute Stroke study (DUST), a prospective multi-centre cohort study including adult patients with acute ischemic stroke within nine hours after symptom onset between May 2009 and July 2013. The design, eligibility criteria, and neuroimaging protocol have been reported previously [8]. All patients underwent non-contrast CT, CT perfusion, and CT angiography (CTA) within 9 hours after symptom onset. In this substudy, we included patients with visible intracranial arterial occlusion on admission CTA, and follow-up vascular imaging at 3 (±2) days. Patients who received intra-arterial treatment were excluded. Body temperature was recorded on admission.

Stroke severity at admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). Stroke subtype was recorded according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Recanalization was assessed on follow-up vascular imaging and classified as no recanalization on the one hand, or partial or complete recanalization on the other. All scans were centrally evaluated by one of three experienced observers, who were blinded for the clinical data except for the side of symptoms. Poor functional outcome was defined as a modified Rankin Scale (mRS) score ≥3 at 90 days.

Temperature data were retrospectively collected from patients’ charts by one investigator, blinded for outcome measures. Body temperature on admission was defined as first recorded body temperature within twelve hours after admission, measured either tympanic or rectal.

The medical ethics committee of the University Medical Center Utrecht approved the DUST study, and written informed consent was obtained from each patient or a legal representative.

Results

Of the 1393 patients in DUST, 643 had an occluded intracranial artery on admission CTA. Reasons for exclusion for the present study were: no follow-up vascular imaging (n = 289), no admission body temperature recorded (n = 30), or intra-arterial treatment (n = 46). We included 278 patients, with 288 occluded intracranial arteries. Patient characteristics are presented in Table 1.

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Table 1. Patient characteristics.

https://doi.org/10.1371/journal.pone.0140777.t001

Location of the most proximal part of the intracranial occlusion was middle cerebral artery in 215 (75%) arteries, posterior cerebral artery in 30 (10%), the intracranial part of the internal carotid artery in 18 (6%), anterior cerebral artery in 10 (4%), basilar artery in 8 (3%), and another artery in 7 (2%) patients. Ten patients had more than one occluded intracranial arteries.

Patients without follow-up imaging were older than patients with follow-up imaging (68 versus 65, P = 0.01), had higher NIHSS scores on admission (13 versus 11, P = 0.01), and had worse outcomes (median mRS 3 versus 2, P<0.001).

Follow-up imaging was performed at a median of 3 days (IQR 2 days) after admission. Follow-up imaging was CTA (95%) or MR angiography (5%). Recanalization occurred in 229 (80%) of occluded arteries. Partial or complete recanalization was associated with a better outcome compared to no recanalization (median mRS 2 (IQR 3) versus 3 (IQR2), respectively; P = 0.01).

Body temperature on admission was not associated with recanalization (OR per 0.1°C, 0.98; 95%CI, 0.93–1.03; P = 0.39; adjusted OR (aOR) per 0.1°C, 0.99; 95%CI, 0.94–1.05; P = 0.70) (Table 2, Fig 1), nor with poor outcome (OR per 0.1°C, 0.97; 95%CI, 0.93–1.01; P = 0.09).

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Fig 1. Odds ratios for the relation between body temperature on admission and recanalization.

https://doi.org/10.1371/journal.pone.0140777.g001

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Table 2. Results of unadjusted and adjusted logistic regression on the relation between body temperature and recanalization.

https://doi.org/10.1371/journal.pone.0140777.t002

Because follow-up imaging was missing in a substantial proportion of patients who were otherwise eligible for our study, we performed post-hoc analyses that modelled several scenarios in these patients. In these post-hoc analyses, we included all patients with a visible intracranial arterial occlusion on admission CTA, with or without follow up imaging. Patients who received intra-arterial treatment were excluded. In a best case scenario assuming that all patients without follow-up imaging had recanalization, body temperature on admission was not associated with recanalization (aOR per 0.1°C, 0.99; 95%CI, 0.95–1.04; P = 0.67). The same was found in a worst case scenario assuming that none of the patients without follow-up imaging had recanalization (aOR per 0.1°C, 1.01; 95%CI, 0.98–1.04; P = 0.50).

Results stratified by time of the second (follow-up) CT angiography are shown in S3 Table.

Discussion

Our findings suggest that in patients with acute ischaemic stroke, there is no relation between body temperature on admission and recanalization of an occluded intracranial artery three days later, irrespective of treatment with alteplase.

Most reports on the relation between body temperature and clot lysis concern in vitro studies. These have shown a reduced rate of fibrinolysis by alteplase at lower temperatures [3]. However, in vitro studies may not adequately reflect the in vivo setting of an acute arterial occlusion. Data from animal and human studies are limited. Some clinical studies found an association between higher admission body temperatures and a favourable outcome after thrombolysis with alteplase [9, 10], but others did not [11]. No studies have investigated whether this was related to higher recanalization rates.

We did not find a relation between body temperature on admission and recanalization or functional outcome. Other studies have suggested that increased body temperatures in the first few days, rather than on admission, are related to poor outcome [12, 13].

This study has limitations. Body temperature was assessed at admission and recanalization at three (± 2) days. Recanalization occurring after several hours may be of little or no benefit to ischemic tissue, and clinical consequences of delayed recanalization are therefore limited [1]. Previous studies suggest that body temperatures during the first three days may also have affected recanalization rates [14, 15]. However, in this study recanalization was strongly related to alteplase treatment within 4.5 hours, suggesting that most recanalization occurs in the first hours after stroke, and recanalization was associated with improved clinical outcome. The generalizability of our findings is hampered because in numerous patients missed follow-up imaging, but this is unlikely to have a major effect on the findings in this explanatory rather than prognostic study. We did not have data on the occurrence of infections in our population. The inter- or intra-observer variability in the measurement of recanalization was also not determined.Finally, the vast majority of our study population had normal body temperatures. Due to the limited variability in body temperatures, we could not assess associations between recanalization and body temperatures below 36.0°C or above 37.5°C.

Supporting Information

Acknowledgments

The Dutch acute stroke trial (DUST) investigators are: Majoie CB, Roos YB, Academic Medical Center, Amsterdam, The Netherlands; Duijm LE, Keizer K, Catharina Hospital, Eindhoven, The Netherlands; van der Lugt A, Dippel DW, Erasmus Medical Center, Rotterdam, The Netherlands; Droogh—de Greve KE, Bienfait HP, Gelre Hospitals, Apeldoorn, The Netherlands; van Walderveen MA, Wermer MJ, Leiden University Medical Center, Leiden, The Netherlands; Lycklama à Nijeholt GJ, Boiten J, Medical Center Haaglanden, The Hague, The Netherlands; Duyndam D, Kwa VI, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands; Meijer FJ, van Dijk EJ, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Kesselring FO, Hofmeijer J, Rijnstate Hospital, Arnhem, The Netherlands; Vos JA, Schonewille WJ, St. Antonius Hospital, Nieuwegein, The Netherlands; van Rooij WJ, de Kort PL, St. Elisabeth Hospital, Tilburg, The Netherlands; Pleiter CC, Bakker SL, St. Franciscus Hospital, Rotterdam, The Netherlands; Bot J, Visser MC, VU Medical Center, Amsterdam, The Netherlands; Velthuis BK*, van der Schaaf IC, Dankbaar JW, Mali WP, van Seeters T, Horsch AD, Niesten JM, Biessels GJ, Kappelle LJ, Luitse MJ, van der Graaf Y, University Medical Center Utrecht, Utrecht, The Netherlands.

* Lead author of this group

E-mail address: b.k.velthuis@umcutrecht.nl