Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Reduced Concussion Symptom Burden in Early Adolescent Athletes Using a Head-Neck Cooling Device.

OBJECTIVE: To determine whether an investigational head-neck cooling device, Pro2cool, can better reduce symptom severity compared with standard postconcussion care in early adolescent athletes after a sports-related concussion. DESIGN: Prospective, longitudinal, randomized trial design conducted over a 28-day period. SETTING: Six pediatric medical centers in Ohio and Michigan. PARTICIPANTS: The study enrolled 167 male and female 12- to 19-year-old athletes who experienced a sports-related concussion within 8 days of study enrollment and registering a Sports Concussion Assessment Tool 5 (SCAT5) composite score >7. INTERVENTIONS: Pro2cool, an investigational head-neck cooling therapy device, was applied at 2 postinjury time points compared with postconcussion standard of care only. MAIN OUTCOME MEASURES: Baseline SCAT5 composite symptom severity scores were determined for all subjects. Sports Concussion Assessment Tool 5 scores for concussed athletes receiving cooling treatment were analyzed across 6 independent postenrollment time points compared with subjects who did not receive cooling therapy and only standard care. Adverse reactions and participate demographics were also compared. RESULTS: Athletes who received Pro2cool cooling therapy (n = 79) experienced a 14.4% greater reduction in SCAT5 symptom severity scores at the initial visit posttreatment, a 25.5% greater reduction at the 72-hour visit posttreatment, and a 3.4% greater reduction at the 10-day visit compared with subjects receiving only standard care (n = 88). Overall, 36 adverse events (increased blood pressure, decreased pulse, and dizziness) were reported, with 13 events associated with the device, of which 3 were classified as moderate in severity. CONCLUSIONS: This study demonstrates the efficacy and safety of head and neck cooling for the management of concussion symptoms in adolescent athletes of an age group for which little to no prior data are available.

Preliminary Safety and Efficacy of Head and Neck Cooling Therapy After Concussion in Adolescent Athletes: A Randomized Pilot Trial.

OBJECTIVE: To determine the safety and efficacy of head and neck cooling when applied up to 8 days after concussion among adolescent athletes. DESIGN: A randomized nonblinded pilot trial. SETTING: Sports Medicine Clinic in a tertiary hospital. PATIENTS: Adolescent athletes aged 12 to 17 years diagnosed with a concussion within 1 week of injury. INTERVENTIONS AND MAIN OUTCOME MEASURES: The control group (n = 27) received standard treatment (short term brain rest), whereas the treatment group (n = 28) received standard treatment and head and neck cooling. Head and neck cooling treatment was applied to patients at the postinjury assessment visit and at 72 hours post-injury. The SCAT5 (Sport Concussion Assessment Tool) total symptom severity score was collected at postinjury assessment visit, pre- and post-treatment at 72 hours, and at 10 days, and 4 weeks post-treatment. RESULTS: Athletes who received head and neck cooling had a faster symptom recovery ( P = 0.003) and experienced significant reduction in symptom severity scores after treatment ( P < 0.001). Sport type and gender did not influence the treatment outcome ( P = 0.447 and 0.940, respectively). CONCLUSIONS: This pilot study demonstrates feasibility of head and neck cooling for the management of acute concussion in adolescent athletes.