Targeted Temperature Management After In-Hospital Cardiac Arrest

Study Overview
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Brief Summary
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The purpose of this study is to determine whether targeted temperature management at 36.0˚C(TTM-36) in patients who remain unconscious after resuscitation from in-hospital cardiac arrest(IHCA) will reduce death and disability compared with fever control. For this purpose, the current pilot study will be undertaken to establish the feasibility, safety, and surrogate outcomes of hypoxic-ischemic brain injury in 60 patients who remain unconscious after resuscitation from IHCA. Eligible patients will be randomly assigned in a 2:1 ratio to either TTM-36(n=40) or conventional treatment group(n=20). Randomization will be performed with stratification according to initial rhythm (shockable vs. non-shockable).

Official Title
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Targeted Temperature Management at 36℃ After In-Hospital Cardiac Arrest Trial(TTM36-IHCA Trial): An Investigator-Initiated, Single-Center, Randomized, Controlled, Assessor-Blinded, Pilot Clinical Trial

Conditions
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Hypoxic Ischemic Encephalopathy

Intervention / Treatment
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* Device: Arctic Sun®
* Device: Arcticgel™
* Procedure: Conventional antipyretic treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-80 years In-hospital cardiac arrest requiring chest compression for > 2 minutes Sustained restoration of spontaneous circulation(ROSC) for > 20 minutes after cardiopulmonary resuscitation(CPR) Unresponsive state(lack of meaningful response to verbal commands) for > 20 minutes after sustained ROSC Informed consents from a patient's family member Exclusion Criteria: Unavailable TTM within 2 hours after ROSC CPR duration > 30 minutes Unwitnessed arrest with initial rhythm asystole Under or planned for extracorporeal membrane oxygenation(ECMO) Initial body temperature < 33 °C Preexisting terminal illness with life expectancy <6 months Pre-admission CPC score of 3-5 Pre-admission mRS score 4-6 Unresponsive(stupor or coma) before cardiac arrest Suspected or confirmed cause of cardiac arrest is diseases of the central nervous system, such as stroke, brain tumor, or amyotrophic lateral sclerosis Any condition in which direct skin surface cooling would be contraindicated, such as large burns, unhealed surgical wounds, decubitus ulcers, cellulitis, or other conditions with disrupted skin integrity Active massive bleeding Major surgery within last 48 hours Cardiothoracic surgery within 14 days Planned surgery within next 72 hours after ROSC Enrolled in other clinical trials Pregnant women Do-not-resuscitate(DNR) state Patients whose family or treating physicians refuse to join this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TTM-36<br>Participants assigned to TTM-36 Arm will be managed by Arcticgel™ and Arctic Sun® to maintain core temperatureTemperature at 36.0℃ for 72 hours. After targeted temperature management(TTM), Fever will be controlled for remaining 7 days by conventional antipyretic treatment. (Treat core temperature ≥ 38.3℃). A total of 40 participants will be enrolled. | Device: Arctic Sun®<br>* Core temperature is maintained to 36℃ for 3 days by using the skin attached pad(Arcticgel™) and targeted temperature management(Arctic Sun®).<br>* Other names: Temperature Management System Model 5000;Device: Arcticgel™<br> <br> * Other names: Hydrogel Coated Pad;Procedure: Conventional antipyretic treatment<br>* Conventional antipyretic treatment for fever includes using of antipyretics, ice packs, circulating fan, and tepid bathing, etc.<br>|
| Active Comparator: Conventional treatment<br>Participants who are assigned to this Arm will be treated with conventional antipyretic treatment regarding the occurrence fever for 7 days.(Treat core temperature ≥ 38.3℃). A total of 20 participants will be enrolled. | Procedure: Conventional antipyretic treatment<br>* Conventional antipyretic treatment for fever includes using of antipyretics, ice packs, circulating fan, and tepid bathing, etc.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combination of death and poor neurological function defined as a Cerebral Performance Category (CPC) score 3 to 5 at 180 days | Efficacy of targeted temperature management at 36.0℃(TTM-36) will be assessed by using Cerebral Performance Category(CPC) score. CPC score is the surrogate outcome for hypoxic-ischemic brain injury. | day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The CPC score 3 to 5 at day 7 and at day 30 |  | day 7, day 30 | 
| The highest levels of serum neuron specific enolase(NSE) during the first 5 days |  | up to day 5 | 
| Unfavorable Electroencephalography(EEG) patterns | Generalized suppression(≤20 μV) Burst-suppression with generalized epileptiform activity Generalized periodic epileptiform discharges on a flat background No EEG reactivity Electrographical seizures Electrographical status epilepticus | day 0, day 4 | 
| Assessment of magnetic resonance imaging(MRI) at day 4 | Total magnetic resonance imaging(MRI) scores The percentage of brain volume with Afferent Diffusion Coefficient(ADC) values < 650 x 10^-6mm^2/sec The percentage of brain volume with ADC values < 450 x 10^-6mm^2/sec Number of cerebral microbleeds | day 4 | 
| Modified Rankin Scale(mRS) score 4 to 6 at day 30 and at Day 180 |  | day 30, day 180 | 
| All-cause mortality at day 30, at Day 180 |  | up to day 180 | 
| Myoclonic or tonic-clonic seizures or status epilepticus(SE) |  | up to day 7 | 
| Neurological status estimated by the Seoul Neurosychological Screeninig Battery (SNSB) 2nd ed. | Attention: Digit span (forward), digit span (backward) Language & related function: Spontaneous speech, comprehension, repetition, reading, writing, finger naming, body part identification, right-left orientation, calculation; BNT (Boston Naming Test) Visuospatial: RCFT (Rey Complex Figure Test) copy score Memory: SVLT (Seoul Verbal Learning Test), RCFT (immediate recall, delayed recall, recognition) Frontal & executive function: COWAT (Controlled Oral Word Association Test), CWST (Color Word Stroop Test), DSC (Digit Symbol Coding), TMT (Trail making test) General cognitive index: MMSE (Mini Mental State Examination), CDR (Clinical Dementia Rating), GDS (Global Deterioration Scale) Activities of daily living (ADL): Barthel index | day 180 | 
| Other neurological evaluations | Depression: BDI (Beck Depression Inventory) Quality of life: SF-36 (Short-Form 36-item Health Survey) Activities of daily life: S-IADL (Seoul-Instrumental Activities of Daily Living) Psychiatric symptoms: NPI (Neuropsychiatric Inventory) Cognition: IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly) Parkinsonism: UPDRS (Unified Parkinson's Disease Rating Scale) Ataxia: ICARS (International Cooperative Ataxia Rating Scale) | day 180 | 
| Assessment of follow-up MRI | Resting state functional MRI: Connectivity strength, proportional increase of connectivity strength on resting state Diffusion tensor imaging: Global mean diffusivity, gray matter mean diffusivity, white matter mean diffusivity , mean fractional anisotropy, proportional increase of white matter global fractional anisotropy, proportional increase of white matter global mean diffusivity High resolution T1-weighted imaging for MRI volumetric: Mean volume of the brain, mean volume of the gray matter of the brain, mean volume of the white matter of the brain, proportional increase of mean volume of the brain, proportional increase of mean volume of the gray matter, proportional increase of mean volume of the white matter Susceptibility-weighted imaging: Number of cerebral microbleeds | day 30 & day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Targeted Temperature Management(TTM), in-hospital cardiac arrest(IHCA), restoration of spontaneous circulation(ROSC), unconsciousness, brain injury