Gisela Lilja

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

BACKGROUND Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

Long-term neurological outcome after cardiac arrest and therapeutic hypothermia

AIM OF THE STUDY To analyse the neurological status of survivors after cardiac arrest (CA) treated with hypothermia. METHODS We prospectively included all patients with CA treated with hypothermia at intensive care units (ICU) in two university hospitals and one regional hospital. All adult survivors at 6 months after CA, n=48, were invited for neurological follow-up and 43 accepted. History, clinical status, ability testing and questionnaires were administered to screen for difficulties, including Assessment of Motor and Process Skills, Neurobehavioral Cognitive Status Examination, Frontal Lobe Assessment Battery, EQ-VAS quality of life scale, Skåne Sleep Index, Hospital Anxiety and Depression Rating Scale, Self-reported Montgomery and Astrand Depression Rating Scale, Global Deterioration Scale, Rivermead Behavioural Memory Test, and the Cerebral Performance Categories (CPC). RESULTS No patient was found to be in a chronic vegetative state and all patients were living at home, one with extensive help. Thirty-six patients were in CPC1 at follow-up, and some degree of neurological sequelae was found in 40 patients, but was mild in all but 3. Three patients had no subjective complaints, nor could any deficits be detected. Initial defects improved over-time. Short-term memory loss, executive frontal lobe dysfunction along with mild depression and sleep rhythm disturbances were the most common findings. CONCLUSIONS Mild cognitive impairment is common following hypothermia-treated cardiac arrest but has little effect on activities of daily living or quality of life.

Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial

IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33°C vs 36°C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales. TRIAL REGISTRATION ClinicalTrials.gov NCT01020916.

Cognitive Function in Survivors of Out-of-Hospital Cardiac Arrest After Target Temperature Management at 33°C Versus 36°C

Background— Target temperature management is recommended as a neuroprotective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors have not been investigated sufficiently. The primary aim of this study was to evaluate whether a target temperature of 33°C compared with 36°C was favorable for cognitive function; the secondary aim was to describe cognitive impairment in cardiac arrest survivors in general. Methods and Results— Study sites included 652 cardiac arrest survivors originally randomized and stratified for site to temperature control at 33°C or 36°C within the Target Temperature Management trial. Survival until 180 days after the arrest was 52% (33°C, n=178/328; 36°C, n=164/324). Survivors were invited to a face-to-face follow-up, and 287 cardiac arrest survivors (33°C, n=148/36°C, n=139) were assessed with tests for memory (Rivermead Behavioural Memory Test), executive functions (Frontal Assessment Battery), and attention/mental speed (Symbol Digit Modalities Test). A control group of 119 matched patients hospitalized for acute ST-segment–elevation myocardial infarction without cardiac arrest performed the same assessments. Half of the cardiac arrest survivors had cognitive impairment, which was mostly mild. Cognitive outcome did not differ (P>0.30) between the 2 temperature groups (33°C/36°C). Compared with control subjects with ST-segment–elevation myocardial infarction, attention/mental speed was more affected among cardiac arrest patients, but results for memory and executive functioning were similar. Conclusions— Cognitive function was comparable in survivors of out-of-hospital cardiac arrest when a temperature of 33°C and 36°C was targeted. Cognitive impairment detected in cardiac arrest survivors was also common in matched control subjects with ST-segment–elevation myocardial infarction not having had a cardiac arrest. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01946932.

Anxiety and depression among out-of-hospital cardiac arrest survivors

AIM Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA-survivors. METHODS OHCA-survivors randomized to targeted temperature of 33 °C or 36 °C within the Target Temperature Management trial (TTM-trial) attended a follow-up after 6 months that included the questionnaire Hospital Anxiety and Depression Scale (HADS). A control group with ST-elevation myocardial infarction (STEMI) completed the same follow-up. Correlations to variables assumed to be associated with anxiety and depression in OHCA-survivors were tested. RESULTS At follow-up 278 OHCA-survivors and 119 STEMI-controls completed the HADS where 24% of OHCA-survivors (28% in 33 °C group/22% in 36 °C group, p=0.83) and 19% of the STEMI-controls reported symptoms of anxiety (OR 1.32; 95% CI (0.78-2.25), p=0.30). Depressive symptoms were reported by 13% of OHCA-survivors (equal in both intervention groups, p=0.96) and 8% of STEMI-controls (OR 1.76; 95% CI (0.82-3.79), p=0.15). Anxiety and depression among OHCA-survivors correlated to Health-Related Quality-of-Life, and subjectively reported cognitive deterioration by patient or observer. In addition, depression was associated with a poor neurological outcome. CONCLUSION One fourth of OHCA-survivors reported symptoms of anxiety and/or depression at 6 months which was similar to STEMI-controls and previous normative data. Subjective cognitive problems were associated with an increased risk for psychological distress. Since psychological distress affects long-term prognosis of cardiac patients in general it should be addressed during follow-up of survivors with OHCA due to a cardiac cause. ClinicalTrials.gov NCT01020916/NCT01946932.

Postanoxic status epilepticus can be identified and treatment guided successfully by continuous electroencephalography.

Prognostication after cardiac arrest and therapeutic hypothermia is challenging. Recent data indicate that a subgroup of patients with postanoxic status epilepticus may recover. We describe a case of postanoxic status epilepticus with good outcome where a multimodal prognostic strategy motivated active and prolonged treatment. Our patient was a 61-year-old woman resuscitated from out-of-hospital cardiac arrest, treated with hypothermia, and monitored with continuous electroencephalography (EEG). Shortly after rewarming, 44 hours after cardiac arrest, electrographic status epilepticus developed and was manifested clinically by myoclonic seizures several hours later. Treatment was guided by continuous simplified EEG monitoring. Conventional antiepileptics were ineffective, and prolonged sedation was necessary to prevent recurrence. Magnetic resonance imaging, somatosensory evoked potentials, and repeated measurements of neuron-specific enolase were unremarkable and did not indicate a poor prognosis. Rather, the EEG characteristics suggested a potential for recovery, and therefore the patient was actively treated until recovery 3 weeks later. At follow-up after 4.5 months, she had only minor neurological sequels. We conclude that a favorable neurological outcome is possible despite prolonged postanoxic status epilepticus. A multimodal strategy for prognostication may help identify treatable cases. Continuous EEG monitoring is an important tool to detect and guide treatment of postanoxic status epilepticus.

Cognitive function after cardiac arrest and temperature management; rationale and description of a sub-study in the Target Temperature Management trial

BackgroundMild to moderate cognitive impairment is common amongst long-term survivors of cardiac arrest. In the Target Temperature Management trial (TTM-trial) comatose survivors were randomized to 33°C or 36°C temperature control for 24 hours after cardiac arrest and the effects on survival and neurological outcome assessed. This protocol describes a sub-study of the TTM-trial investigating cognitive dysfunction and its consequences for patients’ and relatives’ daily life.Methods/DesignSub-study sites in five European countries included surviving TTM patients 180 days after cardiac arrest. In addition to the instruments for neurological function used in the main trial, sub-study patients were specifically tested for difficulties with memory (Rivermead Behavioural Memory Test), attention (Symbol Digit Modalities Test) and executive function (Frontal Assessment Battery). Cognitive impairments will be related to the patients’ degree of participation in society (Mayo-Portland Adaptability Inventory-4), health related quality of life (Short Form Questionnaire–36v2©), and the caregivers’ situation (Zarit Burden Interview©). The two intervention groups (33°C and 36°C) will be compared with a group of myocardial infarction controls.DiscussionThis large international sub-study of a randomized controlled trial will focus on mild to moderate cognitive impairment and its consequences for cardiac arrest survivors and their caregivers. By using an additional battery of tests we may be able to detect more subtle differences in cognitive function between the two intervention groups than identified in the main study. The results of the study could be used to develop a relevant screening model for cognitive dysfunction after cardiac arrest.Trial registrationClinicalTrials.gov: NCT01946932.

Follow-up of cardiac arrest survivors : Why, how, and when? a practical approach

Abstract Cardiac arrest (CA) survivors may experience cognitive, physical, or emotional problems that can affect their return to everyday activities and quality of life. To improve long‐term outcomes, interventions after hospital discharge may be needed. A follow‐up plan to identify CA survivors with increased risk of residual cognitive, physical, or emotional problems is important to target interventions and support. Current recommendations suggest that follow‐up should include screening of potential problems, sharing information, and relevant referrals when needed. The complexity of the follow‐up of CA survivors is due to the fact that several pathways of care may be offered, focusing either on the cardiovascular disease, the postintensive care syndrome, or CA‐related brain injury. There is a potential to improve recovery through a more collaborative and holistic approach to follow‐up. The aim of this review is to give examples of why follow‐up after CA should be provided, but also how and when follow‐up could be performed.

Return to Work and Participation in Society After Out-of-Hospital Cardiac Arrest

Background: The aim of this study was to describe out-of-hospital cardiac arrest (OHCA) survivors’ ability to participate in activities of everyday life and society, including return to work. The specific aim was to evaluate potential effects of cognitive impairment. Methods and Results: Two hundred eighty-seven OHCA survivors included in the TTM trial (Target Temperature Management) and 119 matched control patients with ST-segment–elevation myocardial infarction participated in a follow-up 180 days post-event that included assessments of participation, return to work, emotional problems, and cognitive impairment. On the Mayo-Portland Adaptability Inventory-4 Participation Index, OHCA survivors (n=270) reported more restricted participation In everyday life and in society (47% versus 30%; P<0.001) compared with ST-segment–elevation myocardial infarction controls (n=118). Furthermore, 27% (n=36) of pre-event working OHCA survivors (n=135) compared with 7% (n=3) of pre-event working ST-segment–elevation myocardial infarction controls (n=45) were on sick leave (odds ratio, 4.9; 95% confidence interval, 1.4–16.8; P=0.01). Among the OHCA survivors assumed to return to work (n=135), those with cognitive impairment (n=55) were 3× more likely (odds ratio, 3.3; 95% confidence interval, 1.2–9.3; P=0.02) to be on sick leave compared with those without cognitive impairment (n=40; 36%, n=20, versus 15%, n=6). For OHCA survivors, the variables that were found most predictive for a lower participation were depression, restricted mobility, memory impairment, novel problem-solving difficulties, fatigue, and slower processing speed. Conclusions: OHCA survivors reported a more restricted societal participation 6 months post-arrest, and their return to work was lower compared with ST-segment–elevation myocardial infarction controls. Cognitive impairment was significantly associated with lower participation, together with the closely related symptoms of fatigue, depression, and restricted mobility. These predictive variables may be used during follow-up to identify OHCA survivors at risk of a less successful recovery that may benefit from further support and rehabilitation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01946932.

COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation

Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow.