Selective brain cooling: Let us have a moment of science

Abstract

Selective brain cooling is a promising advent for reducing final infarct volume and improving outcomes in ischemic stroke victims. Despite the robust body of evidence from animal studies, evidence supporting the use of selective hypothermia in stroke patients is lacking. A recent study provided promising results on the safety and possible efficacy of selective brain hypothermia via intraarterial infusion of cooled saline. Better understanding of the patients’ population that may attain benefit from this approach will be informative. Details of infarct progression using perfusion imaging will also help understand the mechanism of effect of selective hypothermia to inform future trials.

Despite recent advances in ischemic stroke reperfusion therapies, a significant proportion of stroke patients with large vessel occlusions sustain disabling deficits. ¹ To date, no neuroprotective agent has been shown to reliably improve stroke outcomes, ² although some promising agents are undergoing testing (ClinicalTrials.gov Identifier: NCT02930018).

Compelling evidence supports the efficacy of hypothermia in experimental models. ³ However, multiple smaller scale studies using systemic cooling could not replicate these effects in stroke patients. ⁴ Potential reasons include the challenges associated with systemic cooling application (up to 10 h to reach target temperature) and the multiple side effects that can occur, e.g. pneumonia (reported in 50% of patients) and shivering. ⁵ Selective brain cooling is promising to achieve rapid induction of brain cooling, even within minutes of infusing cooled saline, while avoiding many of the complications associated with systemic hypothermia. ⁶

A recent paper by Wu et al. ⁷ is among the first to show the safety and feasibility of selective intraarterial hypothermia in stroke patients. The authors prospectively selected 113 patients undergoing mechanical stroke thrombectomy to receive focal cooling pre-reperfusion (10 cc/min normal saline at 4℃ via microcatheter placed distal to the occlusion site for 5 min) followed by cooling using the guide catheter of 30 cc/min normal saline at 4℃ for 10 min, once reperfusion is achieved.

The concept of a brief pre-reperfusion cooling followed by longer reperfusion cooling is of interest and potentially has merits. However, it can be argued that even a brief delay in reperfusion can have negative impact on patients’ outcomes ⁸ and would require more data to support its benefit before its wide implementation can be justified. Another drawback of cooling prior to reperfusion is the potential negative effect of temperature drop on alteplase enzymatic activity, estimated at about 20% activity reduction at 33℃. ⁴ This issue may become more relevant if mechanical thrombectomy fails to achieve reperfusion or if distal embolization occurs after reperfusion in branches that are too distal to be reached via mechanical means.

The authors required a baseline Alberta Stroke Program Early CT score (ASPECTS) of 7 or less, or the presence of poor collaterals for patients’ inclusion. However, the median ASPECTS in the total group was 9: 8 in the cooling group and 9 in the control group. In addition, CT perfusion was performed on a total of 30 patients (11 intervention arm and 19 controls, Table 1). It would be informative to compare the initial core volume (Cerebral Blood Flow (CBF)<20% threshold) with final infarct volume in the two subsets to correct for any baseline variability in infarct volumes. It will be instructive to report if this relatively brief duration of local cooling reduced the infarct growth, after adjustment for initial core volume defined by perfusion.

The authors are encouraged to report the final TICI 2b/3 (and TICI 2c/3) rates in the two arms of the study, and especially for the n=11 and n=19 CTP subgroups. Successful reperfusion is among the strongest predictors of final infarct volume. ⁹

It will also be informative to know whether longer post-reperfusion cooling (e.g. 30 min rather than 10 min) was considered. Evidence from basic studies suggest greater benefit of hypothermia with longer duration and more depth of cooling. ¹⁰

These details will provide better understanding of the underlying mechanism and effects of this approach to selective brain cooling. It will also help estimating the expected effect size, for future trials using this approach.