Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia.
BACKGROUND
Both caffeinol and hypothermia are neuroprotective in preclinical models of transient middle cerebral artery occlusion. We tested whether combining caffeinol and hypothermia with tissue plasminogen activator (t-PA) in patients with acute stroke is safe and feasible.


METHODS
Twenty patients with acute ischemic stroke were treated with caffeinol (caffeine 8-9 mg/kg + ethanol 0.4 g/kg intravenously [IV] x 2 hours, started by 4 hours after symptom onset) and hypothermia (started by 5 hours and continued for 24 hours [target temperature 33-35 degrees C] followed by 12 hours of rewarming). IV t-PA was given to eligible patients. Meperidine and buspirone were used to suppress shivering.


RESULTS
All patients received caffeinol, and most reached target blood levels. Cooling was attempted in 18 patients via endovascular (n = 8) or surface (n = 10) approaches. Two patients were not cooled due to catheter or machine failure. Thirteen patients reached target temperature; average time from symptom onset was 9 hours and 43 minutes. The last 5 hypothermia patients received surface cooling with iced saline induction and larger doses of meperidine; all patients reached target temperature, on average within 2 hours and 30 minutes from induction and 6 hours and 21 minutes from symptom onset. Three patients died: one from symptomatic hemorrhage, one from malignant cerebral edema, and one from unrelated medical complications. No adverse events were attributed to caffeinol. One patient had reduced respiratory drive due to meperidine, requiring BiPAP.


CONCLUSIONS
Combining caffeinol with hypothermia in patients with acute stroke given IV t-PA is feasible. A prospective placebo-controlled randomized study is needed to further assess safety and to test the efficacy of caffeinol, hypothermia, or both.
Martin-Schild
Sheryl
S
Department of Neurology, University of Texas-Houston Medical School, Houston, TX, USA.
Hallevi
Hen
H
Shaltoni
Hashem
H
Barreto
Andrew D
AD
Gonzales
Nicole R
NR
Aronowski
Jarek
J
Savitz
Sean I
SI
Grotta
James C
JC
D000208:Acute Disease / Q000628:therapy; D000759:Adjuvants, Anesthesia / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014151:Anti-Anxiety Agents / Q000008:administration & dosage; D002545:Brain Ischemia / Q000503:physiopathology / Q000628:therapy*; D002065:Buspirone / Q000008:administration & dosage; D002110:Caffeine / Q000008:administration & dosage*; D004338:Drug Combinations; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D008614:Meperidine / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010865:Pilot Projects; D012768:Shivering / Q000187:drug effects; D020521:Stroke / Q000503:physiopathology / Q000628:therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage; D016896:Treatment Outcome
D000759:Adjuvants, Anesthesia; D014151:Anti-Anxiety Agents; D004338:Drug Combinations; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; C503306:caffeinol; D002110:Caffeine; D000431:Ethanol; D008614:Meperidine; D010959:Tissue Plasminogen Activator; D002065:Buspirone