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.

BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA. METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes. RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance. CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.

Serum tau fragments as predictors of death or poor neurological outcome after out-of-hospital cardiac arrest.

Background: Anoxic brain injury is the primary cause of death after resuscitation from out-of-hospital cardiac arrest (OHCA) and prognostication is challenging. The aim of this study was to evaluate the potential of two fragments of tau as serum biomarkers for neurological outcome. Methods: Single-center sub-study of 171 patients included in the Target Temperature Management (TTM) Trial randomly assigned to TTM at 33 °C or TTM at 36 °C for 24 h after OHCA. Fragments (tau-A and tau-C) of the neuronal protein tau were measured in serum 24, 48 and 72 h after OHCA. The primary endpoint was neurological outcome. Results: Median (quartile 1 - quartile 3) tau-A (ng/ml) values were 58 (43-71) versus 51 (43-67), 72 (57-84) versus 71 (59-82) and 76 (61-92) versus 75 (64-89) for good versus unfavourable outcome at 24, 48 and 72 h, respectively (pgroup = 0.95). Median tau C (ng/ml) values were 38 (29-50) versus 36 (29-49), 49 (38-58) versus 48 (33-59) and 48 (39-59) versus 48 (36-62) (pgroup = 0.95). Tau-A and tau-C did not predict neurological outcome (area under the receiver-operating curve at 48 h; tau-A: 0.51 and tau-C: 0.51). Conclusions: Serum levels of tau fragments were unable to predict neurological outcome after OHCA.

The association between plasma miR-122-5p release pattern at admission and all-cause mortality or shock after out-of-hospital cardiac arrest.

BACKGROUND: Data suggests that the plasma levels of the liver-specific miR-122-5p might both be a marker of cardiogenic shock and a prognostic marker of out-of-hospital cardiac arrest (OHCA). Our aim was to characterize plasma miR-122-5p at admission after OHCA and to assess the association between miR-122-5p and relevant clinical factors such all-cause mortality and shock at admission after OHCA. METHODS: In the pilot trial, 10 survivors after OHCA were compared to 10 age- and sex-matched controls. In the main trial, 167 unconscious survivors of OHCA from the Targeted Temperature Management (TTM) trial were included. RESULTS: In the pilot trial, plasma miR-122-5p at admission after OHCA was 400-fold elevated compared to controls. In the main trial, plasma miR-122-5p at admission was independently associated with lactate and bystander cardiopulmonary resuscitation. miR-122-5p at admission was not associated with shock at admission (p = 0.14) or all-cause mortality (p = 0.35). Target temperature (33 °C vs 36 °C) was not associated with miR-122-5p levels at any time point. CONCLUSIONS: After OHCA, miR-122-5p demonstrated a marked acute increase in plasma and was independently associated with lactate and bystander resuscitation. However, miR-122-5p at admission was not associated with all-cause mortality or shock at admission.

Importance of comorbidities in comatose survivors of shockable and non-shockable out-of-hospital cardiac arrest treated with target temperature management.

OBJECTIVE: Comorbidity prior to out-of-hospital cardiac arrest (OHCA) and primary rhythm in relation to survival is not well established. We aimed to assess the prognostic importance of comorbidity in relation to primary rhythm in OHCA-patients treated with Target Temperature Management (TTM). DESIGN: Consecutive comatose survivors of OHCA treated with TTM in hospitals in the Copenhagen area between 2002-2011 were included. Utstein-based pre- and in-hospital data collection was performed. Data on comorbidity was obtained from The Danish National Patient Register and patient charts, assessed by the Charlson Comorbidity Index (CCI). RESULTS: A total of 666 patients were included. A third (n = 233, 35%) presented with non-shockable rhythm, and they were less often male (64% vs. 82%, p < .001), and OHCA in public, witnessed OHCA, and bystander cardiopulmonary resuscitation (CPR) were less common compared to patients with a shockable primary rhythm (public: 27% vs. 48%, p < .001, witnessed: 79% vs. 90%, p < .001, bystander CPR: 47% vs. 63%, p < .001). 30-day mortality was 62% compared to 28% in patients with non-shockable and shockable rhythm, respectively. By Cox-regression analyses, any comorbidity (CCI ≥1) was the only factor independently associated with 30-day mortality in patients with non-shockable rhythm (HR =1.9 (95% CI: 1.2-2.9), p < .01), whereas in patients with shockable rhythm comorbidity was not associated with outcome after adjustment for prognostic factors (HR = 0.82 (0.55-1.2), p = .34). No significant interaction between primary rhythm and comorbidity in terms of mortality was present. CONCLUSION: A higher comorbidity burden was independently associated with a higher 30-day mortality rate in patients presenting with non-shockable primary rhythm but not in patients with shockable rhythm.

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.

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.).

Atrial Fibrillation Following Out-of-Hospital Cardiac Arrest and Targeted Temperature Management-Are We Giving It the Attention it Deserves?

OBJECTIVES: Atrial fibrillation has been associated with increased mortality in the general population and mixed populations of critical ill. Atrial fibrillation can also affect patients during post-cardiac arrest care. We sought to assess the prognostic implications of atrial fibrillation following out-of-hospital cardiac arrest, including relation to the level of targeted temperature management. DESIGN: A post hoc analysis of a prospective randomized trial. SETTING: Thirty-six ICUs. PATIENTS: We included 897 (96%) of the 939 comatose out-of-hospital cardiac arrest survivors from the targeted temperature management trial (year, 2010-2013) with data on heart rhythm on day 2. INTERVENTIONS: Targeted temperature management at 33°C or 36°C. MEASUREMENTS AND MAIN RESULTS: Endpoints included cumulative proportion of atrial fibrillation following out-of-hospital cardiac arrest and 180-day all-cause mortality and specific death causes stratified by atrial fibrillation. Atrial fibrillation on day 2 was used as primary endpoint analyses to exclude effects of short-term atrial fibrillation related to resuscitation and initial management. The cumulative proportions of atrial fibrillation were 15% and 11% on days 1 and 2, respectively. Forty-three percent of patients with initial atrial fibrillation the first day were reported with sinus rhythm on day 2. No difference was found between the groups treated with targeted temperature management at 33°C and 36°C. Patients affected by atrial fibrillation had significantly higher 180-day mortality (atrial fibrillation: 66% vs no-atrial fibrillation: 43%; plogrank < 0.0001 and unadjusted hazard ratio, 1.75 [1.35-2.30]; p < 0.0001). The association between atrial fibrillation and higher mortality remained significant (adjusted hazard ratio, 1.34 [1.01-1.79]; p < 0.05) adjusted for potential confounders. Atrial fibrillation was independently associated with increased risk of cardiovascular death and multiple-organ failure (adjusted hazard ratio, 2.07 [1.39-3.09]; p < 0.001), whereas no association with higher risk of death from cerebral causes was found. CONCLUSIONS: Atrial fibrillation was independently associated with higher mortality, primarily driven by cardiovascular causes and multiple-organ failure, and may thus identify a vulnerable subpopulation. Whether treatment to prevent atrial fibrillation is associated with an improved prognosis remains to be established.

Bradycardia During Targeted Temperature Management: An Early Marker of Lower Mortality and Favorable Neurologic Outcome in Comatose Out-of-Hospital Cardiac Arrest Patients.

OBJECTIVES: Bradycardia is common during targeted temperature management, likely being a physiologic response to lower body temperature, and has recently been associated with favorable outcome following out-of-hospital cardiac arrest in smaller observational studies. The present study sought to confirm this finding in a large multicenter cohort of patients treated with targeted temperature management at 33°C and explore the response to targeted temperature management targeting 36°C. DESIGN: Post hoc analysis of a prospective randomized study. SETTING: Thirty-six ICUs in 10 countries. PATIENTS: We studied 447 (targeted temperature management = 33°C) and 430 (targeted temperature management = 36°C) comatose out-of-hospital cardiac arrest patients with available heart rate data, randomly assigned in the targeted temperature management trial from 2010 to 2013. INTERVENTIONS: Targeted temperature management at 33°C and 36°C. MEASUREMENTS AND MAIN RESULTS: Endpoints were 180-day mortality and unfavorable neurologic function (cerebral performance category 3-5). Patients were stratified by target temperature and minimum heart rate during targeted temperature management (< 50, 50-59, and ≥ 60 beats/min [reference]) at 12, 20, and 28 hours after randomization. Heart rates less than 50 beats/min and 50-59 beats/min were recorded in 132 (30%) and 131 (29%) of the 33°C group, respectively. Crude 180-day mortality increased with increasing minimum heart rate (< 50 beats/min = 32%, 50-59 beats/min = 43%, and ≥ 60 beats/min = 60%; p(log-rank) < 0.0001). Bradycardia less than 50 beats/min was independently associated with lower 180-day mortality (hazard ratio(adjusted) = 0.50 [0.34-0.74; p < 0.001]) and lower odds of unfavorable neurologic outcome (odds ratio(adjusted) = 0.38 [ 0.21-0.68; p < 0.01]) in models adjusting for potential confounders including age, initial rhythm, time to return of spontaneous circulation, and lactate at admission. Similar, albeit less strong, independent associations of lower heart rates and favorable outcome were found in patients treated with targeted temperature management at 36°C. CONCLUSIONS: This study confirms an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large cohort of comatose out-of-hospital cardiac arrest patients treated by targeted temperature management at 33°C. Bradycardia during targeted temperature management at 33°C may thus be a novel, early marker of favorable outcome.

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial.

OBJECTIVES: Whole-body ischemia during out-of-hospital cardiac arrest triggers immediate activation of inflammatory systems leading to a sepsis-like syndrome. The aim was to investigate the association between level of systemic inflammation and mortality in survivors after out-of-hospital cardiac arrest treated with targeted temperature management. DESIGN: Post hoc analysis. SETTING: Single-center study of a prospective multicenter randomized study. PATIENTS: One hundred sixty-nine patients (99%) with available blood samples out of 171 patients included in the Target Temperature Management trial, randomly assigning patients to targeted temperature management at 33°C or 36°C. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: At baseline and 24, 48, and 72 hours after out-of-hospital cardiac arrest, blood samples were obtained and screened for a battery of inflammatory markers. Level of interleukin-1ß, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, interleukin-12, interleukin-13, tumor necrosis factor-α, interferon-γ, C-reactive protein, and procalcitonin were measured. Mortality at 30 days was evaluated by Cox analysis, and the predictive capability of inflammatory markers was evaluated by area under the curve. Level of all inflammatory markers changed significantly within 72 hours after out-of-hospital cardiac arrest (all p values<0.001), but only procalcitonin levels showed overall differences between nonsurvivors and survivors (p=0.0002). At baseline, interleukin-6 was independently associated with mortality, whereas both interleukin-6 levels (hazard ratio=1.23 [1.01-1.49]; p=0.04) and procalcitonin levels (hazard ratio=1.20 [1.03-1.39]; p=0.02) 24 hours after out-of-hospital cardiac arrest were associated with 30-day mortality with no interactions between targeted temperature management group and levels of interleukin-6 (p=0.25) or procalcitonin (p=0.85). None of the other inflammatory markers were independently associated with mortality. Area under the curve for procalcitonin and interleukin-6, 24 hours after out-of-hospital cardiac arrest, were 0.74 and 0.63, respectively. CONCLUSIONS: Level of inflammation, assessed by interleukin-6 and procalcitonin, was independently associated with increased mortality with the highest discriminative value obtained 24 hours after out-of-hospital cardiac arrest. Interventions aiming at decreasing level of inflammation as a way to improve outcome may be investigated in future studies.

Hemodynamics and vasopressor support during targeted temperature management at 33°C Versus 36°C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial*.

OBJECTIVE: To investigate the hemodynamic profile associated with different target temperatures and to assess the prognostic implication of inotropic/vasopressor support and mean arterial pressure after out-of-hospital cardiac arrest. There is a lack of information how different target temperatures may affect hemodynamics. DESIGN: Post hoc analysis of a prospective randomized study. SETTING: Thirty-six ICUs in 10 countries. PATIENTS: Nine hundred twenty patients (97%) with available vasopressor data out of 950 patients from the Target Temperature Management trial randomly assigned patients to a targeted temperature management at 33 °C or 36 °C. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure, heart rate, and lactate were registered at prespecified time points. The population was stratified according to cardiovascular Sequential Organ Failure Assessment = 4 defining the high vasopressor group and cardiovascular Sequential Organ Failure Assessment less than or equal to 3 defining the low vasopressor group. The targeted temperature management 33 (TTM33) group had a hemodynamic profile with lower heart rate (-7.0 min(-1) [95% confidence limit, -8.7, -5.1]; p(group) < 0.0001), similar mean arterial pressure (-1.1 mm Hg [95% confidence limit, -2.3, 0.2]; p(group) = 0.10), and increased lactate (0.6 mmol/L [95% confidence limit, 0.3, 0.8]; p(group) < 0.0001) compared with the targeted temperature management 36 (TTM36) group. A cardiovascular Sequential Organ Failure Assessment score = 4 was recorded in 54% versus 45%, p = 0.03 in the TTM33 and the TTM36 group, respectively. The high vasopressor group carried a 53% mortality rate when compared with a 34% in the low vasopressor group, p(log-rank) less than 0.0001, with an adjusted hazard ratio of 1.38 (95% CI, 1.11-1.71; p = 0.004). There was no interaction between vasopressor group and allocated target temperature group (p = 0.40). An inverse relationship between mean arterial pressure and mortality was identified (p = 0.0008). CONCLUSIONS: Targeted temperature management at 33 °C was associated with hemodynamic alterations with decreased heart rate, elevated levels of lactate, and need for increased vasopressor support compared with targeted temperature management at 36 °C. Low mean arterial pressure and need for high doses of vasopressors were associated with increased mortality independent of allocated targeted temperature management.

Factors Associated With Successful Resuscitation After Out-of-Hospital Cardiac Arrest and Temporal Trends in Survival and Comorbidity.

STUDY OBJECTIVE: Out-of-hospital cardiac arrest has an overall poor prognosis. We sought to identify what temporal trends and influencing factors existed for this condition in one region. METHODS: We studied consecutive out-of-hospital cardiac arrest patients from 2007 to 2011 with attempted resuscitation in Copenhagen. From an Utstein database, we assessed survival to admission and comorbidity with the Charlson comorbidity index from the National Patient Registry and employment status from the Danish Rational Economic Agents Model database. We used logistic regression analyses to identify factors associated with outcome. RESULTS: Of a total of 2,527 attempted resuscitations in out-of-hospital cardiac arrest patients, 40% (n=1,015) were successfully resuscitated and admitted to the hospital. The strongest independent factors associated with successful resuscitation were shockable primary rhythm (multivariate odds ratio [OR]=3.9; 95% confidence interval [CI] 3.1 to 5.0), witnessed arrest (multivariate OR=3.5; 95% CI 2.7 to 4.6), and out-of-hospital cardiac arrest in a public area (multivariate OR=2.1; 95% CI 1.6 to 2.8), whereas no comorbidity (multivariate OR=1.1; 95% CI 0.8 to 1.45), sex (multivariate OR=1.14; 95% CI 0.91 to 1.44), and employment status (multivariate OR=1.17; 95% CI 0.89 to 1.56) were not independently associated with outcome. The number of patients with a high comorbidity burden (Charlson comorbidity index ≥3) increased during the study period (P trend <.001), from 18% to 31% (P trend <.001), whereas the percentage of out-of-hospital cardiac arrest patients with successful resuscitation to hospital admission increased by 3% per year during the study period, from 37% in 2007 to 43% in 2011 (P trend <.001). CONCLUSION: Our observations confirm the importance of key features that influence out-of-hospital cardiac arrest survival to hospital admission but are not highly influenced by public health actions. Despite increased illness burden, this short term outcome from cardiac arrest improved as care system efforts matured.

Relationships between biomarkers and left ventricular filling pressures at rest and during exercise in patients after myocardial infarction.

BACKGROUND: Increased pulmonary capillary wedge pressure (PCWP) is an independent prognostic predictor after myocardial infarction (MI), but PCWP is difficult to assess noninvasively in subjects with preserved ejection fraction (EF). We hypothesized that biomarkers would provide information regarding PCWP at rest and during exercise in subjects with preserved EF after MI. METHODS AND RESULTS: Seventy-four subjects with EF >45% and recent MI underwent right heart catheterization at rest and during a symptom-limited semisupine cycle exercise test with simultaneous echocardiography. Plasma samples were collected at rest for assessment of midregional pro-A-type natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), copeptin, and midregional pro-adrenomedullin (MR-proADM). Plasma levels of MR-proANP and PCWP were associated at rest (r = 0.33; P = .002) and peak exercise (r = 0.35; P = .002) as well as with changes in PCWP (r = 0.26; P = .03). Plasma levels of NT-proBNP and PCWP were weakly associated at rest (r = 0.23; P = .03) and peak exercise (r = 0.28; P = .02) but not with changes in PCWP (r = 0.20; P = .09). In a multivariable analysis, plasma levels of MR-proANP remained associated with rest and exercise PCWP (P < .01), whereas NT-proBNP did not. Plasma levels of Gal-3, copeptin, and MR-proADM were not associated with PCWP at rest or peak exercise. CONCLUSIONS: In subjects recovering from an acute MI with preserved EF, plasma levels of natriuretic peptides, particularly MR-proANP, are associated with filling pressures at rest and during exercise.

Soluble Urokinase-Type Plasminogen Activator Receptor in Comatose Survivors After Out-of-Hospital Cardiac Arrest Treated with Targeted Temperature Management.

Exposure to whole-body ischemia/reperfusion after out-of-hospital cardiac arrest (OHCA) triggers a systemic inflammatory response where soluble urokinase plasminogen activator receptor (suPAR) is released. This study investigated serial levels of suPAR in differentiated target temperature management and the associations with mortality and 6-month neurological outcome. This is a single-center substudy of the randomized Targeted Temperature Management (TTM) for 24-hour versus 48-hour trial. In this analysis, we included 82 patients and measured serial levels of suPAR at 24, 48, and 72 hours after achievement of target temperature (32-34°C). We assessed all-cause mortality and neurological function evaluated by the Cerebral Performance Categories (CPC) at 6 months after OHCA. Levels of suPAR between TTH groups were evaluated in repeated measures mixed models. Mortality was assessed by the Kaplan-Meier method and serial measurements of suPAR (log2 transformed) were investigated by Cox proportional-hazards models. Good neurological outcome at 6 months was assessed by logistic regression analyses. Levels of suPAR were significantly different between TTH groups (pinteraction = 0.04) with the highest difference at 48 hours, 4.7 ng/mL (95% CI: 4.1-5.4 ng/mL) in the TTH24 group compared to 2.8 ng/mL (95% CI: 2.2-3.5 ng/mL) in the TTH48 group, p < 0.0001. Levels of suPAR above the median value were significantly associated with increased all-cause mortality at any time point (plog-rank<0.05). The interaction of suPAR levels and TTH group was not significant (pinteraction = NS). A twofold increase in levels of suPAR was significantly associated with a decreased odds ratio of a good neurological outcome in both unadjusted and adjusted analyses without interaction of TTH group (pinteraction = NS). Prolonged TTM of 48 hours versus 24 hours was associated with lower levels of suPAR. High levels of suPAR were associated with increased mortality and lower odds for good neurological outcome at 6 months with no significant interaction of TTH group.

The Effect of Targeted Temperature Management on the Metabolome Following Out-of-Hospital Cardiac Arrest.

Targeted temperature management (TTM) may moderate the injury from out-of-hospital cardiac arrest. Slowing the metabolism has been a suggested effect. Nevertheless, studies have found higher lactate levels in patients cooled to 33°C compared with 36°C even days from TTM cessation. Larger studies have not been performed on the TTM's effect on the metabolome. Accordingly, to explore the effect of TTM, we used ultra-performance liquid-mass spectrometry in a substudy of 146 patients randomized in the TTM trial to either 33°C or 36°C for 24 hours and quantified 60 circulating metabolites at the time of hospital arrival (T0) and 48 hours later (T48). From T0 to T48, profound changes to the metabolome were observed: tricarboxylic acid (TCA) cycle metabolites, amino acids, uric acid, and carnitine species all decreased. TTM significantly modified these changes in nine metabolites (Benjamini-Hochberg corrected false discovery rate <0.05): branched amino acids valine and leucine levels dropped more in the 33°C arm (change [95% confidence interval]: -60.9 µM [-70.8 to -50.9] vs. -36.0 µM [-45.8 to -26.3] and -35.5 µM [-43.1 to -27.8] vs. -21.2 µM [-28.7 to -13.6], respectively), whereas the TCA metabolites including malic acid and 2-oxoglutaric acid remained higher for the first 48 hours (-7.7 µM [-9.7 to -5.7] vs. -10.4 µM [-12.4 to -8.4] and -3 µM [-4.3 to -1.7] vs. -3.7 µM [-5 to -2.3]). Prostaglandin E2 only dropped in the TTM 36°C group. The results show that TTM affects the metabolism hours after normothermia have been reached. Clinical Trial Number: NCT01020916.

Target Temperature Management after out-of-hospital cardiac arrest--a randomized, parallel-group, assessor-blinded clinical trial--rationale and design.

BACKGROUND: Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. METHODS: The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. DISCUSSION: The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.

Comparing Doppler Echocardiography and Thermodilution for Cardiac Output Measurements in a Contemporary Cohort of Comatose Cardiac Arrest Patients Undergoing Targeted Temperature Management.

Measuring cardiac output is used to guide treatment during postresuscitation care. The aim of this study was to compare Doppler echocardiography (Doppler-CO) with thermodilution using pulmonary artery catheters (PAC-CO) for cardiac output estimation in a large cohort of comatose out-of-hospital cardiac arrest (OHCA) patients undergoing targeted temperature management (TTM). Single-center substudy of 141 patients included in the TTM trial randomly assigned to 33 or 36°C for 24 hours after OHCA. Per protocol, PAC-CO and Doppler-CO were measured simultaneously shortly after admission and again at 24 and 48 hours. Linear correlation was assessed between methods and positive predictive value (PPV) and negative predictive value (NPV) of Doppler to estimate low cardiac output (<3.5 L/min) was calculated. A total of 301 paired cardiac output measurements were available. Average cardiac output was 5.28 ± 1.94 L/min measured by thermodilution and 4.06 ± 1.49 L/min measured by Doppler with a mean bias of 1.22 L/min (limits of agreements -1.92 to 4.36 L/min). Correlation between methods was moderate (R2 = 0.36). Using PAC-CO as the gold standard, PPV of a low cardiac output measurement (<3.5 L/min) by Doppler was 33%. However, the NPV was 92%. Hypothermia at 33°C did not negatively affect the correlations of CO methods. In the lowest quartile of Doppler, 13% had elevated lactate (>2 mmol/L). In the lowest quartile of thermodilution, 36% had elevated lactate (>2 mmol/L). In ventilated OHCA patients, the two methods for estimating cardiac output correlated moderately and there was a consistent underestimation of Doppler-CO. Absolute cardiac output values from Doppler-CO should be interpreted with caution. However, Doppler can be used to exclude low cardiac output with high accuracy. TTM at 33°C did not negatively affect the correlation or bias of cardiac output measurements. ClinicalTrials.gov ID: NCT01020916.

Targeted plasma metabolomics in resuscitated comatose out-of-hospital cardiac arrest patients.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death. Even if successfully resuscitated, mortality remains high due to ischemic and reperfusion injury (I/R). The oxygen deprivation leads to a metabolic derangement amplified upon reperfusion resulting in an uncontrolled generation of reactive oxygen species in the mitochondria triggering cell death mechanisms. The understanding of I/R injury in humans following OHCA remains sparse, with no existing treatment to attenuate the reperfusion injury. AIM: To describe metabolic derangement in patients following resuscitated OHCA. METHODS: Plasma from consecutive resuscitated unconscious OHCA patients drawn at hospital admission were analyzed using ultra-performance-liquid-mass-spectrometry. Sixty-one metabolites were prespecified for quantification and studied. RESULTS: In total, 163 patients were included, of which 143 (88%) were men, and the median age was 62 years (53-68). All measured metabolites from the tricarboxylic acid (TCA) cycle were significantly higher in non-survivors vs. survivors (180-days survival). Hierarchical clustering identified four clusters (A-D) of patients with distinct metabolic profiles. Cluster A and B had higher levels of TCA metabolites, amino acids and acylcarnitine species compared to C and D. The mortality was significantly higher in cluster A and B (A:62% and B:59% vs. C:21 % and D:24%, p < 0.001). Cluster A and B had longer time to return of spontaneous circulation (A:33 min (21-43), B:27 min (24-35), C:18 min (13-28), and D:18 min (12-25), p < 0.001). CONCLUSION: Circulating levels of metabolites from the TCA cycle best described the variance between survivors and non-survivors. Four different metabolic phenotypes with significantly different mortality were identified.

MicroRNA-9-3p: a novel predictor of neurological outcome after cardiac arrest.

AIMS: Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose after hospital arrival are at high risk of mortality due to anoxic brain injury. MicroRNA are small-non-coding RNA molecules ultimately involved in gene-silencing. They show promise as biomarkers, as they are stable in body fluids. The microRNA 9-3p (miR-9-3p) is associated with neurological injury in trauma and subarachnoid haemorrhage. METHODS AND RESULTS: This post hoc analysis considered all 171 comatose OHCA patients from a single centre in the target temperature management (TTM) trial. Patients were randomized to TTM at either 33°C or 36°C for 24 h. MicroRNA-9-3p (miR-9-3p) was measured in plasma sampled at admission and at 28, 48, and 72 h. There were no significant differences in age, gender, and pre-hospital data, including lactate level at admission, between miR-9-3p level quartiles. miR-9-3p levels changed markedly following OHCA with a peak at 48 h. Median miR-9-3p levels between TTM 33°C vs. 36°C were not different at any of the four time points. Elevated miR-9-3p levels at 48 h were strongly associated with an unfavourable neurological outcome [OR: 2.21, 95% confidence interval (CI): 1.64-3.15, P < 0.0001). MiR-9-3p was inferior to neuron-specific enolase in predicting functional neurological outcome [area under the curve: 0.79 (95% CI: 0.71-0.87) vs. 0.91 (95% CI: 0.85-0.97)]. CONCLUSION: MiR-9-3p is strongly associated with neurological outcome following OHCA, and the levels of miR-9-3p are peaking 48 hours following cardiac arrest.

Hypothermic versus Normothermic Temperature Control after Cardiac Arrest.

BACKGROUND: The evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics. METHODS: An individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence). RESULTS: The primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups. CONCLUSIONS: Hypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)

Impact of Hypothermia on Oxygenation Variables and Metabolism in Survivors of Out-of-Hospital Cardiac Arrest Undergoing Targeted Temperature Management at 33°C Versus 36°C.

Targeted temperature management (TTM) exerts substantial impact on hemodynamic function in out-of-hospital cardiac arrest (OHCA) patients. Whole-body oxygen consumption (VO2) and delivery (DO2) have not previously been investigated in a clinical setting during TTM at different levels of temperature after OHCA. A substudy of 151 patients randomized at a single center in the TTM-trial, where patients were randomly assigned TTM at 33°C (TTM33) or 36°C (TTM36) for 24 hours. We calculated VO2 according to the principle of Fick (VO2 = cardiac output*arteriovenous oxygen content difference). DO2 was calculated as cardiac output*arterial oxygen content. Cardiac output was measured by pulmonary artery catheter with thermodilution. Arteriovenous oxygen content difference was calculated from arterial and mixed venous oxygen saturation and hemoglobin. Oxygen extraction ratio = VO2/DO2. At 24 hours, the VO2 was 169 ± 59 mL O2 per minute in TTM33 and 217 ± 53 mL O2 per minute in TTM36 (p < 0.0001). During 24 hours of TTM, the overall difference was 53 mL O2 minute (95% confidence interval [CI]: 31-74, pgroup < 0.0001). After rewarming at 36 and 48 hours, there was no difference in VO2 between the groups. DO2 was overall 277 mL O2 per minute (95% CI: 175-379, pgroup < 0.0001) higher in the TTM36-group during TTM. Oxygen extraction ratio during TTM was not significantly different between the two groups (2% [95% CI: -0.1 to 5, pgroup = 0.09]). VO2 during the first 36 hours after OHCA correlated significantly with temperature, and VO2 was 19 mL O2 per minute lower per degree reduction in temperature (95% CI: 15-22), p < 0.0001. TTM at 33°C compared to 36°C after OHCA is associated with significantly lower VO2 and DO2, however, oxygen extraction ratio was not significantly different. For each degree lower body temperature, the VO2 fell by 19 mL O2 per minute.