Stroke is one of the leading causes for death and disability worldwide. The introduction of mechanical thrombectomy (MT) for patients with large-vessel occlusion stroke (LVOS) significantly improved functional outcome and is currently considered the gold standard in this subgroup of stroke patients (1). However, still less than 50% of LVOS patients treated with MT, even despite fast and complete recanalization, achieve functional independence at 90 days and the 90-day mortality rate is approximately 15% (1). Multiple peri-interventional factors influence functional outcome in LVOS patients, leading to a continued development to improve pre-and intrahospital management and to investigate neuroprotective measures in this important subgroup of stroke patients.

Therapeutic hypothermia (TH) has been shown to improve neurological recovery in patients with generalized brain ischemia after out-of-hospital cardiac arrest (2) and is recommended by guidelines in this patient group (3). The effects of TH are multimechanistic, affecting almost every molecular and cellular pathway known to lead to cell death (4). However, the role of TH in the focal brain ischemia associated with stroke remains unclear. Clinical trials examining systemic cooling techniques of stroke patients have failed to show any benefit (5, 6). A meta-analysis including 12 studies did not observe a greater overall improvement in functional outcome in patients with TH in acute ischemic stroke than standard of care, although some studies demonstrated a shift toward better outcomes (7). This might be due to the higher incidence of complications observed in the TH groups, mainly in form of infections and cardiac complications (e.g., bradyarrhythmia) (7). Therefore, neuroprotective effect might be outweighed by cardiac dysfunction and hemodynamic imbalance (8) by increasing catecholamine release and myocardial oxygen demand (9). In addition, the efficacy of TH has been shown to depend on the duration, timing, depth, and kind of application of hypothermia, all of which are not clear in focal cerebral ischemia (10).

Postinterventional hypothermia is a frequent complication in stroke patients after MT, which always is performed in an emergency setting (11). General anesthesia, prolonged MT times, and the fact that the patient lies motionless—in many cases without transurethral catheters—in the angio suite can lead to a quick drop in the patient’s core temperature. In this respect, as many mechanical thrombectomies are performed quickly (12), active warming systems are not widely used. This inadvertent hypothermia might potentially have neuroprotective but also detrimental effects on patients’ outcomes (e.g., increased infection rates or hypothermia-associated coagulopathy). Recent studies analyzing the effect of body temperature on functional outcomes of MT patients were inconclusive. While a study by Hartmann et al. suggested that inadvertent hypothermia after MT had no influence on functional outcome or mortality but is associated with an increased rate of pneumonia and bradyarrhythmia (13), a study by Xu et al. found that lower intraoperative body temperature during MT was independently associated with improved neurological outcome (14).

Given this inconclusive data, this study aimed to determine the rate of hypothermia in LVOS patients receiving MT and to investigate its effect on functional outcomes in a large, prospectively derived stroke database.

Postinterventional hypothermia is a frequent complication in LVOS patients after MT. This inadvertent hypothermia could potentially have neuroprotective but also detrimental effects on patients’ functional outcomes.

In this study, hypothermia after MT was associated with an unfavorable functional outcome. We found a significant association between postinterventional hypothermia and an unfavorable functional outcome at 90 days. In addition, there was a trend for unfavorable functional outcome at discharge and significant results for the NIHSS score at discharge as well as relative change in NIHSS. Our study, therefore, does not support the hypothesis that inadvertent hypothermia in LVOS patients may have neuroprotective effects but might contribute to worse functional outcomes despite successful recanalization. While moderate therapeutic hypothermia has been shown to improve clinical outcomes in patients with cardiac arrest (2, 18) and in animal stroke models (19), clinical studies have failed to show a beneficial effect of induced hypothermia in human stroke patients (5–7, 20, 21). This might be due to the fact that many patients with LVOS have cardiovascular risk factors, and therapeutic hypothermia may further disrupt hemodynamic balance and deteriorate cardiac function (8). Conversely, patients of advanced age and those with overweight or chronic diseases are more likely to develop perioperative hypothermia (22). That is why we adjusted for cardiovascular risk factors as possible confounders.

Inadvertent hypothermia is a common side effect in patients undergoing surgery. It can occur as a result of the suppression of central mechanisms of temperature regulation due to anesthesia and prolonged exposure of large skin surfaces to cold temperatures in operating rooms (23). Perioperative hypothermia has negative effects on coagulation, blood loss and transfusion requirements, metabolization of drugs, surgical site infections, and discharge from the post-anesthesia care unit (24). Active body surface warming (ABSW) systems are effective in maintaining physiological normothermia and are used to prevent adverse clinical outcomes (25). The results of our study underline the importance of ABSW systems to maintain normothermia even with short thrombectomy times.

In the randomized SIESTA trial, hypothermia was associated with the performance of MT under general anesthesia (11). In our study, general anesthesia was associated with an unfavorable functional outcome at 90 days. At the moment, the impact of the type of anesthetic technique on neurological outcomes is still under debate (26). As general anesthesia was associated with worse functional outcomes of MT patients in some other cohorts as well (27), a potential beneficial effect of hypothermia may have been confounded by the performance of general anesthesia in our study. Therefore, we corrected for general anesthesia as a confounder.

In a recent observational study by Hartmann et al. (13) including 416 patients with anterior circulation large-vessel occlusion treated with EVT, approximately half of the patients (50.2%) were hypothermic (<36.0°C; median body temperature 35.2°C) and half were normothermic (36.0°C to 37.5°C; median body temperature 36.4°C) after MT. Patients with temperature > 37.5°C after EVT were excluded. Hypothermia after EVT was associated with higher age and with general anesthesia for EVT, while there was no association with the duration of the procedure. The multivariate outcome analysis could not demonstrate an association of hypothermia with favorable functional outcome (mRS score < 3 at 3 months), which aligns with our results. More hypothermic patients suffered from pneumonia (36.4% vs. 25.6%, p = 0.02) and bradyarrhythmia (52.6% vs. 16.4%, p < 0.001), whereas there was no significant difference in thromboembolic events.

As in our study, Hartmann et al. address inadvertent hypothermia and not induced hypothermia as a possible neuroprotective approach. In both studies, inadvertent hypothermia might be a surrogate marker for worse medical pre-condition and more severely affected stroke patients, despite correcting for possible confounders in multivariate analysis. This may have restricted the ability to detect a possible neuroprotective effect.

For acute ischemic stroke patients with LVOS, EVT is a highly effective therapy (1). Therefore, additional therapy effects in EVT patients might be difficult to find out. To avoid the side effects of systemic hypothermia, selective brain cooling using endovascular cooling catheters combined with endovascular reperfusion might be a promising approach (28). For selective intra-arterial cold saline infusion, feasibility and safety were demonstrated in a pilot trial by Chen et al. (29).

The negative influence of higher body temperature on post-procedural infarction growth and functional outcome of MT patients has already been described (30, 31). Consistently, in our study rates of postinterventional hyperthermia were higher in patients with unfavorable functional outcomes. However, infarct volume and expansion were not available in our dataset.

An important limitation of the study is the demonstration of an association; it is not possible to show causality. Hypothermia might be an epiphenomenon of worse functional outcomes caused by an imbalance in comorbidities and/or nutritional status (cachexia, sarcopenia, pre-stroke functional status). In addition, hypothermia might be an indicator of longer procedural delays and durations of mechanical thrombectomy. Therefore, we corrected for cardiovascular risk factors and treatment times. Another limitation is the lack of a control group with active warming of the patients and the monocentric design of the study. The strength of the study is the detailed analysis of a prospectively derived databank and the control for multiple possible confounders.

Further studies are needed to evaluate the effects of the combination of targeted temperature management and MT in acute ischemic stroke patients in randomized clinical trials. Until then, since hypothermia, as well as hyperthermia, were shown to be associated with an unfavorable clinical outcome, we suggest maintaining strict normothermia in LVOS patients treated with MT using active body surface warming (ABSW) systems.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of University Medicine Göttingen (reference number: 13/7/15). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Ka: Writing – review & editing, Writing – original draft, Visualization, Project administration, Methodology, Investigation, Formal analysis, Data curation. FK: Writing – review & editing, Visualization, Methodology, Investigation, Data curation. AJ: Writing – review & editing, Data curation. ME: Writing – review & editing, Data curation. NK-S: Writing – review & editing. M-NP: Writing – review & editing. IM: Writing – review & editing, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.