Neuropsychological Outcome After Cardiac Arrest

Neuropsychological Outcome After Cardiac Arrest: A Prospective Case Control Sub-study of the Targeted Hypothermia Versus Targeted Normothermia After out-of Hospital Cardiac Arrest Trial (TTM2)

This study is a sub-study to the large pragmatic Target Temperature Management 2 Trial (TTM2-trial, ClinicalTrials.gov Identifier: NCT02908308), assessing effectiveness of controlled hypothermia after out-of-hospital cardiac arrest (OHCA).

This study is designed to provide detailed information on cognition after OHCA and its relationship to associated factors as emotional function, fatigue, and sleep. A secondary aim is to utilize this information to validate a neurocognitive screening battery used 6 months after OHCA in the TTM2-trial.

Approximately 7 and 24 months after OHCA, survivors at selected TTM2 study sites will perform a standardized neuropsychological assessment including performance-based tests of cognition and questionnaires of behavioral and emotional function, fatigue, and insomnia. At 1:1 ratio, a control group of myocardial infarction (MI) patients but no occurrence of cardiac arrest will be recruited and perform the same test battery. Group differences at 7 and 24 months will be analyzed per cognitive domain (verbal, visual/constructive, short-term working memory, episodic memory, processing speed, executive functions). Results of the OHCA survivors on the TTM2 neurocognitive screening battery will be compared with neuropsychological test results at 7 months time.

Study Overview

• Status: Completed
• Conditions: Fatigue; Insomnia; Cognition Disorders; Psychological Distress; Hypoxia-Ischemia, Brain; Heart Arrest, Out-Of-Hospital
• Intervention / Treatment: Diagnostic test: Neuropsychological assessment

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
• Sweden
  • Göteborg, Sweden
    • Sahlgrenska University Hospital
  • Halmstad, Sweden
    • Halmstad County Hospital
  • Helsingborg, Sweden
    • Helsingborg Hospital
  • Lund, Sweden
    • Skane University Hospital
  • Malmö, Sweden
    • Skane University Hospital
• United Kingdom
  • Essex
    • Basildon, Essex, United Kingdom
      • The Essex Cardiothoracic Centre, Basildon and Thurrock University Hospitals NHS Foundation Trust
  • Wales
    • Cardiff, Wales, United Kingdom
      • University Hospital of Wales, Cardiff and Vale University Health Board

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

OHCA survivors at TTM2-sites participating in this study. Survivors are invited to partake in this study at the regular six-month follow-up of the TTM2-trial.

The cohort of MI patients acting as controls are recruited and assessed at one participating site per country through quality registers.

Description

Inclusion Criteria:

• OHCA of a presumed cardiac or unknown cause (OHCA cohort only)
• Sustained return of spontaneous circulation (ROSC) during intensive care - defined as 20 minutes with signs of circulation without the need for chest compressions (OHCA cohort only)
• Unconsciousness - defined as not being able to obey verbal commands (FOUR-score motor response of <4) and no verbal response to pain after sustained ROSC (OHCA cohort only)
• Inclusion within 180 minutes of ROSC (OHCA cohort only)
• During intensive care - eligible for intensive care without restrictions or limitations (OHCA cohort only)
• MI with performed coronary angiography (MI cohort only)

Exclusion Criteria:

• Temperature on admission <30°C (OHCA cohort only)
• On extracorporeal membrane oxygenation (ECMO) prior to return of spontaneous circulation (OHCA cohort only)
• Obvious or suspected pregnancy
• Intracranial bleeding (OHCA cohort only)
• Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy
• Clinical dementia diagnosis before the event
• Inability to speak the local language well enough to complete the assessment without assistance from an interpreter
• Inability to meet for a face-to-face examination
• Clinical Frailty Scale Index ≥8, indicating very severe frailty
• Cardiac arrest before or in connection with MI (MI cohort only)
• Active substance abuse

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cardiac Arrest survivors; Cardiac arrest survivors at selected TTM2-sites only.	Diagnostic test: Neuropsychological assessment; Standardized neuropsychological battery consisting of the following tests and questionnaires: Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) Vocabulary, Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency, WAIS-IV Block Design, WAIS-IV Matrix Reasoning, WAIS-IV Digit Span, Wechsler Memory Scale - Third Edition (WMS-III) Spatial Span, Rey Auditory Verbal Learning Test (RAVLT), WMS-III Logical Memory, Brief Visuospatial Memory Test-Revised (BVMT-R), Trail Making Test (TMT) A & B, D-KEFS Color Word Interference Test, Behavioral Assessment of the Dysexecutive Syndrome Dysexecutive Questionnaire (BADS DEX), Multidimensional Fatigue Inventory (MFI-20), Minimal Insomnia Symptom Scale (MISS), Hospital Anxiety and Depression Scale (HADS).
Myocardial Infarction patients; A control group from a cohort of patients with myocardial infarction with performed coronary angiography but no occurrence of cardiac arrest will be recruited at 1:1 ratio.	Diagnostic test: Neuropsychological assessment; Standardized neuropsychological battery consisting of the following tests and questionnaires: Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) Vocabulary, Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency, WAIS-IV Block Design, WAIS-IV Matrix Reasoning, WAIS-IV Digit Span, Wechsler Memory Scale - Third Edition (WMS-III) Spatial Span, Rey Auditory Verbal Learning Test (RAVLT), WMS-III Logical Memory, Brief Visuospatial Memory Test-Revised (BVMT-R), Trail Making Test (TMT) A & B, D-KEFS Color Word Interference Test, Behavioral Assessment of the Dysexecutive Syndrome Dysexecutive Questionnaire (BADS DEX), Multidimensional Fatigue Inventory (MFI-20), Minimal Insomnia Symptom Scale (MISS), Hospital Anxiety and Depression Scale (HADS).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive impairment	Cognitive function in OHCA and MI patients, using composite z-scores from the neuropsychological tests grouped by cognitive domain.	7 months after the cardiac event

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity and specificity of the neurocognitive screening battery in the main TTM2-trial	Validation of the neurocognitive screening battery in OHCA patients, using the detailed neuropsychological test battery as a gold standard with sensitivity and specificity analyses. Here, patients will be considered to have a cognitive impairment if they meet any of the following criteria on the neuropsychological tests: 1) an impaired composite z-score defined as z ≤ - 1.65 in at least one cognitive domain; 2) z ≤ - 1.65 in at least two scores used for cognitive domain calculation. Cut-scores for indicated impairment on the neurocognitive screening battery will be < 26 on the MoCA, z≤-1 on the SDMT, ≥3.08 on the IQCODE-CA and the answer "no" to question 2 at the TSQ.	7 months post-arrest

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cognitive function	Longitudinal change in cognitive function in OHCA and MI patients, analyzed with a mixed model regression.	7 months, 24 months after the cardiac event

Collaborators and Investigators

• Sponsor: Region Skane
• Collaborators: Lund University; Aarhus University Hospital; Sahlgrenska University Hospital, Sweden; Mid and South Essex NHS Foundation Trust; Cardiff and Vale University Health Board; Halmstad County Hospital
• Investigators: Study Director: Niklas Nielsen, MD, PhD, Lund University; Study Director: Gisela Lilja, PhD, OT, Lund University; Study Director: Tobias Cronberg, MD, PhD, Lund University; Study Director: Susanna Vestberg, PhD, Lic.Psych., Lund University; Principal Investigator: Erik Blennow Nordström, PhD, Lic.Psych., Lund University

Publications and helpful links

General Publications

• Blennow Nordstrom E, Lilja G, Vestberg S, Ullen S, Friberg H, Nielsen N, Heimburg K, Evald L, Mion M, Segerstrom M, Grejs AM, Keeble T, Kirkegaard H, Ljung H, Rose S, Wise MP, Rylander C, Unden J, Cronberg T. Neuropsychological outcome after cardiac arrest: a prospective case control sub-study of the Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest trial (TTM2). BMC Cardiovasc Disord. 2020 Oct 7;20(1):439. doi: 10.1186/s12872-020-01721-9.
• Blennow Nordstrom E, Vestberg S, Evald L, Mion M, Segerstrom M, Ullen S, Bro-Jeppesen J, Friberg H, Heimburg K, Grejs AM, Keeble TR, Kirkegaard H, Ljung H, Rose S, Wise MP, Rylander C, Unden J, Nielsen N, Cronberg T, Lilja G. Neuropsychological outcome after cardiac arrest: results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial. Crit Care. 2023 Aug 26;27(1):328. doi: 10.1186/s13054-023-04617-0.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2018
• Primary Completion (Actual): January 11, 2021
• Study Completion (Actual): May 23, 2022

Study Registration Dates

• First Submitted: May 17, 2018
• First Submitted That Met QC Criteria: May 31, 2018
• First Posted (Actual): June 1, 2018

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 15, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Neuropsychology
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Signs and Symptoms, Respiratory; Hypoxia, Brain; Brain Ischemia; Ischemia; Heart Arrest; Cognition Disorders; Hypoxia; Hypoxia-Ischemia, Brain; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: CardiacArrestLundNeuropsych

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No