Date Published: June 1, 2018
Publisher: JKL International LLC
Author(s): Zheng Zhang, Linlei Zhang, Yuchuan Ding, Zhao Han, Xunming Ji.
Ischemic stroke is a major cause of death and disability globally, and its incidence is increasing. The only treatment approved by the US Food and Drug Administration for acute ischemic stroke is thrombolytic treatment with recombinant tissue plasminogen activator. As an alternative, therapeutic hypothermia has shown excellent potential in preclinical and small clinical studies, but it has largely failed in large clinical studies. This has led clinicians to explore the combination of therapeutic hypothermia with other neuroprotective strategies. This review examines preclinical and clinical progress towards developing highly effective combination therapy involving hypothermia for stroke patients.
The combination of diverse neuroprotective strategies with hypothermia has been extensively investigated for the alleviation of ischemic injury arising from cardiac arrest, hypoxic-ischemic encephalopathy or spinal cord impairment. The literature applying such combination therapy to focal stroke is more limited. In addition, studies of such combination therapy often report inconsistent results about the efficacy for treating stroke (Table 2). Several differences among studies may help explain these discrepancies, such as how stroke was modeled, when treatment was initiated relative to stroke, how long treatment lasted, and what was the depth of cooling. As far as neuroprotective drugs are concerned alone, heterogeneity of human stroke and lack of methodological agreement between preclinical and clinical studies may lead to failure of translating experimental success to clinical. Another potential problem is that drug metabolism may differ at cooler temperatures from at normal body temperature. The finding by several studies that combination therapy failed to improve on the results of monotherapy may reflect in some cases a “ceiling effect”: the monotherapy achieved the optimal efficacy, such that additional benefit from the other therapy was undetectable.