Quantitative pupillometry in comatose out-of-hospital cardiac arrest patients: A post-hoc analysis of the TTH48 trial.

BACKGROUND: Quantitative pupillometry is an objective method to examine pupil reaction and subsequently grade the response on a neurological pupil index (NPi) scale from 0 to 5. The aim of the present sub-study was to explore the long-term prognostic value of NPi in comatose out-of-hospital cardiac arrest patients undergoing targeted temperature management (TTM). METHODS: This planned sub-study of the "Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest: A randomized clinical trial." NPi was assessed from admission and throughout day 3 and linked to the Cerebral Performance Categories score at 6 months. We compared the prognostic performance of NPi in 65 patients randomized to a target temperature of 33 ± 1°C for 24 or 48 h. RESULTS: The NPi values were not different between TTM groups (p > .05). When data were pooled, NPi was strongly associated with neurological outcome at day 1 with a mean NPi of 3.6 (95% CI 3.4-3.8) versus NPi 3.9 (3.6-4.1) in the poor versus good outcome group, respectively (p < .01). At day 2, NPi values were 3.6 (3.1-4.0) and 4.1 (3.9-4.2) (p = .01) and at day 3, the values were 3.3 (2.6-4.0) and 4.3 (4.1-4.6), respectively (p < .01). The prognostic ability of NPi, defined by area under the receiver operating characteristic curve was best at day three. CONCLUSION: Quantitative pupillometry measured by NPi was not different in the two TTM groups, but overall, significantly associated with good and poor neurological outcomes at 6 months. NPI has a promising diagnostic accuracy, but larger studies are warranted.

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. Objective: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. Design, Setting, and Participants: This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. Interventions: Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. Main Outcomes and Measures: The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. Results: In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. Of these patients, 69% (120/175) in the 48-hour group had a favorable outcome at 6 months compared with 64% (112/176) in the 24-hour group (difference, 4.9%; 95% CI, -5% to 14.8%; relative risk [RR], 1.08; 95% CI, 0.93-1.25; P = .33). Six-month mortality was 27% (48/175) in the 48-hour group and 34% (60/177) in the 24-hour group (difference, -6.5%; 95% CI, -16.1% to 3.1%; RR, 0.81; 95% CI, 0.59-1.11; P = .19). There was no significant difference in the time to mortality between the 48-hour group and the 24-hour group (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). Adverse events were more common in the 48-hour group (97%) than in the 24-hour group (91%) (difference, 5.6%; 95% CI, 0.6%-10.6%; RR, 1.06; 95% CI, 1.01-1.12; P = .04). The median length of intensive care unit stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group. Conclusions and Relevance: In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. Trial Registration: clinicaltrials.gov Identifier: NCT01689077.

Common patterns of EEG reactivity in post-anoxic coma identified by quantitative analyses.

OBJECTIVE: Description of typical kinds of EEG reactivity (EEG-R) in post-anoxic coma using a quantitative method. METHODS: Study of 101 out-of-hospital cardiac arrest patients, 71 with good outcome (cerebral performance category scale ≤ 2). EEG was recorded 12-24 hours after cardiac arrest and four noxious, one auditory, and one visual stimulation were applied for 30 seconds each. Individual reference intervals for the power in the delta, theta, alpha, and beta bands were calculated based on six 2-second resting epochs just prior to stimulations. EEG-R in consecutive 2-second epochs after stimulation was expressed in Z-scores. RESULTS: EEG-R occurred roughly equally frequent as an increase or as a decrease in EEG activity. Sternal rub and sound stimulation were most provocative with the most pronounced changes as an increase in delta activity 4.5-8.5 seconds after stimulation and a decrease in theta activity 0.5-4.5 seconds after stimulation. These parameters predicted good outcome with an AUC of 0.852 (95 % CI: 0.771-0.932). CONCLUSIONS: Quantitative EEG-R is a feasible method for identification of common types of reactivity, for evaluation of stimulation methods, and for prognostication. SIGNIFICANCE: This method provides an objective measure of EEG-R revealing knowledge about the nature of EEG-R and its use as a diagnostic tool.

MR-proANP and NT-proBNP During Targeted Temperature Management Following Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the TTH48 Trial.

We aimed to evaluate the effect of prolonged targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA) on the levels of midregional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) and assess their potential as prognostic biomarkers. A preplanned post hoc analysis of "Targeted temperature management for 48 h vs 24 h and neurologic outcome after out-of-hospital cardiac arrest: A randomized clinical trial (TTH48 trial)," where patients were randomized to TTM at 33°C ± 1°C of standard duration (24 hours) versus prolonged (48 hours). Blood samples were drawn from patients with OHCA at two Scandinavian university hospitals at admission to the ICU and at 24, 48, and 72 hours after reaching the target temperature. Primary outcome was levels of MR-proANP and NT-proBNP. Secondary outcome was cerebral performance category (CPC 1-5) at 6 months. Samples from 114 patients were analyzed. Prolonged TTM significantly decreased the levels of MR-proANP and NT-proBNP at 48 hours compared with standard 24 hours-TTM (p < 0.01). However, there were no significant differences at other time points. Patients with poor outcome (CPC 3-5) had a statistically significantly increased MR-proANP level at 24 hours (p < 0.01) and 72 hours (p < 0.01) compared with the good outcome group (CPC 1-2). Prognostic performance was best at 24 hours for both MR-proANP and NT-proBNP; with an AUC of 0.73 (confidence interval [95% CI]: 0.63-0.83) and 0.72 (95 % CI: 0.59-0.85), respectively. Prolonged TTM lowered the levels of both MR-proANP and NT-proBNP at 48 hours. MR-proANP may add prognostic information in postcardiac arrest patients. ClinicalTrials.gov ID: NCT01689077.

Biomarker prognostication of cognitive impairment may be feasible even in out-of hospital cardical arrest survivors with good neurological outcome.

BACKGROUND: Patients surviving out-of hospital cardicac arrest, with good neurological outcome according to Cerebral Performance Category, frequently have neuropsychological impairment. We studied whether biomarker data (S-100b and neuron-specific enolase) obtained during the ICU stay predicted cognitive impairment 6 months after resuscitation. METHODS: Patients (N = 79) with a CPC-score ≤2 were recruited from two trial sites taking part in the TTH48 trial comparing targeted temperature management (TTM) for 48 h vs. 24 h at 33 ± 1 °C. We assessed patients 6 months after the OHCA. We measured biomarkers S-100b and NSE at arrival and at 24, 48 and 72 h after reaching the target temperature of 33 ± 1 °C. Four cognitive domain z-scores were calculated, and global cognitive impairment was defined as z < -1.67 on at least 3 out of 13 cognitive tests. Non-parametric correlations were used to assess the relationship between cognitive domain and biomarkers. ROC curves were used to assess prediction of cognitive impairment from the biomarkers. Logistic regression was used to investigate whether TTM duration moderated biomarker prediction of cognitive impairment. RESULTS: Cognitive impairment was present in 22% of the patients with memory impairment being the most common. The biomarkers correlated significantly with several cognitive domain scores and NSE at 48 h predicted cognitive impairment with 100% sensitivity and 56% specificity. The predictive properties of NSE at 48 h was unaffected by duration of TTM. CONCLUSIONS: Early biomarker prognostication of cognitive impairment is feasible even in OHCA survivors with good neurological outcome as defined by CPC. NSE at 48 h predicted cognitive impairment.

Copeptin as a Prognostic Marker in Prolonged Targeted Temperature Management After Out-of-Hospital Cardiac Arrest.

The aim was to investigate blood concentrations of copeptin and the prognostication in 24 versus 48 hours of targeted temperature management (TTM) in patients resuscitated after out-of-hospital cardiac arrest. This is an exploratory biomarker substudy of the trial entitled; "Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital-cardiac-arrest: A randomized clinical trial." Patients were randomized to target temperature of 33°C ± 1°C for 24 (TTM24) or 48 (TTM48) hours. The primary outcome was copeptin concentrations compared with TTM at admission, 24, 48, and 72 hours (t24, t48, and t72) after reaching target temperature. Secondary outcomes were the association between copeptin and cerebral performance category (CPC) score after 6 months, and copeptin level between cerebral or noncerebral causes of death. Blood samples from 117 patients were analyzed from two Scandinavian sites. No significant differences in copeptin concentrations were found between TTM24 versus TTM48 at admission 211.3 µg/L (148-276.6) versus 179.8 µg/L (127-232.6) (p = 0.45), t24: 23.3 µg/L (16.5-30.2) versus 18.6 µg/L (13.3-23.9) (p = 0.25), t48: 28.8 µg/L (20.6-36.9) versus 19.7 µg/L (14.3-25.1) (p = 0.06), and t72: 23.3 µg/L (13.8-26.8) versus 31.6 µg/L (22-41.2) (p = 0.05). Copeptin concentrations were significantly higher in poor neurological outcome group at t24, t48, and t72 (p < 0.01), but not at admission (p = 0.19). The prognostic ability of copeptin (area under the receiver operating characteristic curve) was at admission: 0.59 (95% confidence intervals: 0.46-0.72), t24: 0.74 (0.63-0.86), t48: 0.8 (0.7-0.9), and t72: 0.76 (0.65-0.87). Copeptin levels were not significantly different in noncerebral compared with cerebral causes at admission: p = 0.41, t24: p = 0.52, t48: p = 0.15, and t72: p = 0.38. There were no differences in the level of copeptin in TTM24 versus TTM48. Blood concentrations of copeptin were associated with CPC at 6 months, and no association between levels of copeptin and cerebral versus noncerebral causes of death was observed.

Younger age is associated with higher levels of self-reported affective and cognitive sequelae six months post-cardiac arrest.

BACKGROUND: Affective and cognitive sequelae are frequently reported in cardiac arrest survivors; however, little is known about the risk factors. We assessed the hypothesis that self-reported affective and cognitive sequelae six months after OHCA may be associated with demography, acute care and cerebral outcome. METHODS: This is a sub-study of the multicentre "Target Temperature Management for 48 vs. 24 h and Neurologic Outcome after Out-of-Hospital Cardiac Arrest: A Randomised Clinical Trial" (the TTH48 trial) investigating the effect of prolonged TTM at 33 ±â€¯1 °C. We invited patients with good outcome on the Cerebral Performances Categories (CPC score ≤ 2) to answer questionnaires on anxiety, depression, emotional distress, perceived stress and cognitive failures six months post OHCA. RESULTS: In total 79 of 111 eligible patients were included in the analysis. There were no significant differences in baseline characteristics between the included group and the group lost to follow-up. Younger age was a negative predictor across all self-reported outcomes, even when controlling for gender, ROSC time, treatment allocation, cognitive impairment and global outcome (CPC 1 or 2). Female gender was a predictor of anxiety, though this should be interpreted cautiously as only eight women participated. A CPC score of 2 score was a negative predictor of self-reported affective outcomes, albeit not for self-reported cognitive failures. CONCLUSION: Younger age was associated with higher levels of self-reported affective and cognitive sequelae six months post OHCA. Female gender may be associated with self-reported anxiety. A higher CPC score may be a proxy for self-reported affective sequelae.

Severe or critical hypotension during post cardiac arrest care is associated with factors available on admission - a post hoc analysis of the TTH48 trial.

PURPOSE: We explored whether severe or critical hypotension can be predicted, based on patient and resuscitation characteristics in out-of-hospital cardiac arrest (OHCA) patients. We also explored the association of hypotension with mortality and neurological outcome. MATERIALS AND METHODS: We conducted a post hoc analysis of the TTH48 study (NCT01689077), where 355 out-of-hospital cardiac arrest (OHCA) patients were randomized to targeted temperature management (TTM) treatment at 33 °C for either 24 or 48 h. We recorded hypotension, according to four severity categories, within four days from admission. We used multivariable logistic regression analysis to test association of admission data with severe or critical hypotension. RESULTS: Diabetes mellitus (OR 3.715, 95% CI 1.180-11.692), longer ROSC delay (OR 1.064, 95% CI 1.022-1.108), admission MAP (OR 0.960, 95% CI 0.929-0.991) and non-shockable rhythm (OR 5.307, 95% CI 1.604-17.557) were associated with severe or critical hypotension. Severe or critical hypotension was associated with increased mortality and poor neurological outcome at 6 months. CONCLUSIONS: Diabetes, non-shockable rhythm, longer delay to ROSC and lower admission MAP were predictors of severe or critical hypotension. Severe or critical hypotension was associated with poor outcome.

Echocardiographic parameters during prolonged targeted temperature Management in out-of-hospital Cardiac Arrest Survivors to predict neurological outcome - a post-hoc analysis of the TTH48 trial.

BACKGROUND: Transthoracic echocardiographic (TTE) indices of myocardial function among survivors of out-of-hospital cardiac arrest (OHCA) have been related to neurological outcome; however, results are inconsistent. We hypothesized that changes in average peak systolic mitral annular velocity (s') from 24 h (h) to 72 h following start of targeted temperature management (TTM) predict six-month neurological outcome in comatose OHCA survivors. METHODS: We investigated the association between peak systolic velocity of the mitral plane (s') and six-month neurological outcome in a population of 99 patients from a randomised controlled trial comparing TTM at 33 ± 1 °C for 24 h (h) (n = 47) vs. 48 h (n = 52) following OHCA (TTH48-trial). TTE was conducted at 24 h, 48 h, and 72 h after reaching target temperature. The primary outcome was 180 days neurological outcome assessed by Cerebral Performance Category score (CPC180) and the primary TTE outcome measure was s'. Secondary outcome measures were left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), e', E/e' and tricuspid annular plane systolic excursion (TAPSE). RESULTS: Across all three scan time points s' was not associated with neurological outcome (ORs: 24 h: 1.0 (95%CI: 0.7-1.4, p = 0.98), 48 h: 1.13 (95%CI: 0.9-1.4, p = 0.34), 72 h: 1.04 (95%CI: 0.8-1.4, p = 0.76)). LVEF, GLS, E/e', and TAPSE recorded on serial TTEs following OHCA were neither associated with nor did they predict CPC180. Estimated median e' at 48 h following TTM was 5.74 cm/s (95%CI: 5.27-6.22) in patients with good outcome (CPC180 1-2) vs. 4.95 cm/s (95%CI: 4.37-5.54) in patients with poor outcome (CPC180 3-5) (p = 0.04). CONCLUSIONS: s' assessed on serial TTEs in comatose survivors of OHCA treated with TTM was not associated with CPC180. Our findings suggest that serial TTEs in the early post-resuscitation phase during TTM do not aid the prognostication of neurological outcome following OHCA. TRIAL REGISTRATION: NCT02066753 . Registered 14 February 2014 - Retrospectively registered.

Haemodynamics and vasopressor support during prolonged targeted temperature management for 48 hours after out-of-hospital cardiac arrest: a post hoc substudy of a randomised clinical trial.

BACKGROUND: Comatose patients admitted after out-of-hospital cardiac arrest frequently experience haemodynamic instability and anoxic brain injury. Targeted temperature management is used for neuroprotection; however, targeted temperature management also affects patients' haemodynamic status. This study assessed the haemodynamic status of out-of-hospital cardiac arrest survivors during prolonged (48 hours) targeted temperature management at 33°C. METHODS: Analysis of haemodynamic and vasopressor data from 311 patients included in a randomised, clinical trial conducted in 10 European hospitals (the TTH48 trial). Patients were randomly allocated to targeted temperature management at 33°C for 24 (TTM24) or 48 (TTM48) hours. Vasopressor and haemodynamic data were reported hourly for 72 hours after admission. Vasopressor load was calculated as norepinephrine (µg/kg/min) plus dopamine(µg/kg/min/100) plus epinephrine (µg/kg/min). RESULTS: After 24 hours, mean arterial pressure (mean±SD) was 74±9 versus 75±9 mmHg (P=0.19), heart rate was 57±16 and 55±14 beats/min (P=0.18), vasopressor load was 0.06 (0.03-0.15) versus 0.08 (0.03-0.15) µg/kg/min (P=0.22) for the TTM24 and TTM48 groups, respectively. From 24 to 48 hours, there was no difference in mean arterial pressure (Pgroup=0.32) or lactate (Pgroup=0.20), while heart rate was significantly lower (average difference 5 (95% confidence interval 2-8) beats/min, Pgroup<0.0001) and vasopressor load was significantly higher in the TTM48 group (Pgroup=0.005). In a univariate Cox regression model, high vasopressor load was associated with mortality in univariate analysis (hazard ratio 1.59 (1.05-2.42) P=0.03), but not in multivariate analysis (hazard ratio 0.77 (0.46-1.29) P=0.33). CONCLUSIONS: In this study, prolonged targeted temperature management at 33°C for 48 hours was associated with higher vasopressor requirement but no sign of any detrimental haemodynamic effects.

Haemodynamics and vasopressor support during prolonged targeted temperature management for 48 hours after out-of-hospital cardiac arrest: a post hoc substudy of a randomised clinical trial.

BACKGROUND: Comatose patients admitted after out-of-hospital cardiac arrest frequently experience haemodynamic instability and anoxic brain injury. Targeted temperature management is used for neuroprotection; however, targeted temperature management also affects patients' haemodynamic status. This study assessed the haemodynamic status of out-of-hospital cardiac arrest survivors during prolonged (48 hours) targeted temperature management at 33°C. METHODS: Analysis of haemodynamic and vasopressor data from 311 patients included in a randomised, clinical trial conducted in 10 European hospitals (the TTH48 trial). Patients were randomly allocated to targeted temperature management at 33°C for 24 (TTM24) or 48 (TTM48) hours. Vasopressor and haemodynamic data were reported hourly for 72 hours after admission. Vasopressor load was calculated as norepinephrine (µg/kg/min) plus dopamine(µg/kg/min/100) plus epinephrine (µg/kg/min). RESULTS: After 24 hours, mean arterial pressure (mean±SD) was 74±9 versus 75±9 mmHg (P=0.19), heart rate was 57±16 and 55±14 beats/min (P=0.18), vasopressor load was 0.06 (0.03-0.15) versus 0.08 (0.03-0.15) µg/kg/min (P=0.22) for the TTM24 and TTM48 groups, respectively. From 24 to 48 hours, there was no difference in mean arterial pressure (Pgroup=0.32) or lactate (Pgroup=0.20), while heart rate was significantly lower (average difference 5 (95% confidence interval 2-8) beats/min, Pgroup<0.0001) and vasopressor load was significantly higher in the TTM48 group (Pgroup=0.005). In a univariate Cox regression model, high vasopressor load was associated with mortality in univariate analysis (hazard ratio 1.59 (1.05-2.42) P=0.03), but not in multivariate analysis (hazard ratio 0.77 (0.46-1.29) P=0.33). CONCLUSIONS: In this study, prolonged targeted temperature management at 33°C for 48 hours was associated with higher vasopressor requirement but no sign of any detrimental haemodynamic effects.

The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: A post hoc analysis of the TTH48 trial.

BACKGROUND: Acute kidney injury (AKI) is common after cardiac arrest and targeted temperature management (TTM). The impact of different lengths of cooling on the development of AKI has not been well studied. In this study of patients included in a randomised controlled trial of TTM at 33 °C for 24 versus 48 h after cardiac arrest (TTH48 trial), we examined the influence of prolonged TTM on AKI and the incidence and factors associated with the development of AKI. We also examined the impact of AKI on survival. METHODS: This study was a sub-study of the TTH48 trial, which included patients cooled to 33 ±â€¯1 °C after out-of-hospital cardiac arrest for 24 versus 48 h. AKI was classified according to the KDIGO AKI criteria based on serum creatinine and urine output collected until ICU discharge for a maximum of seven days. Survival was followed for up to six months. The association of admission factors on AKI was analysed with multivariate analysis and the association of AKI on mortality was analysed with Cox regression using the time to AKI as a time-dependent covariate. RESULTS: Of the 349 patients included in the study, 159 (45.5%) developed AKI. There was no significant difference in the incidence, severity or time to AKI between the 24- and 48-h groups. Serum creatinine values had significantly different trajectories for the two groups with a sharp rise occurring during rewarming. Age, time to return of spontaneous circulation, serum creatinine at admission and body mass index were independent predictors of AKI. Patients with AKI had a higher mortality than patients without AKI (hospital mortality 36.5% vs 12.5%, p < 0.001), but only AKI stages 2 and 3 were independently associated with mortality. CONCLUSIONS: We did not find any association between prolonged TTM at 33 °C and the risk of AKI during the first seven days in the ICU. AKI is prevalent after cardiac arrest and TTM and occurs in almost half of all ICU admitted patients and more commonly in the elderly, with an increasing BMI and longer arrest duration. AKI after cardiac arrest is an independent predictor of time to death.

Post resuscitation prognostication by EEG in 24 vs 48 h of targeted temperature management.

OBJECTIVE: To test if prognostic performance is affected by prolonged targeted temperature management (TTM) in comatose out-of-hospital cardiac arrest patients using two recently proposed EEG pattern classification models. METHODS: In this sub-study of the "Target Temperature Management for 48 vs. 24 hand Neurologic Outcome after Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial", EEGs of 20-30 min duration were collected 24 h and 48 h after reaching the target temperature of 33 ±â€¯1 °C. We classified EEGs according to two EEG classification models by Westhall et al. ("highly malignant", "malignant" and "benign") and Hofmeijer et al. ("unfavorable", "intermediate" and "favorable"). We tested prognostic ability against 6 months functional outcome using the Cerebral Performance Category score. RESULTS: We recorded EEGs in 120 patients at 24 h and in 44 patients at 48 h. We found no difference in specificities or sensitivities of the two models between the two TTM groups (all p-values >0.19) or in prognostication at 24 h compared to 48 h (all p-values >0.13), except for the presence of EEG reactivity favoring prognostication at 24 h (p < 0.001). Being classified in the "benign" or "favorable" category was strongly associated with good outcome with specificities of 100% (90-100) and 97% (85-100) for the Westhall and Hofmeijer models respectively. CONCLUSIONS: We found no difference in the prognostic performance of the two studied EEG classification models during prolonged TTM for 48 h compared to standard duration, nor between EEG classification performed at 24 h versus 48 h after reaching target temperature. The two models performed best in good outcome prediction.

Prolonged targeted temperature management reduces memory retrieval deficits six months post-cardiac arrest: A randomised controlled trial.

BACKGROUND: Cognitive sequelae, most frequently memory, attention, and executive dysfunctions, occur commonly in out-of-hospital cardiac arrest (OHCA) survivors. Targeted temperature management (TTM) following OHCA is associated with improved cognitive function. However, the relationship between the duration of TTM and cognitive outcome remains unclear. We hypothesised that OHCA survivors that were subjected to prolonged TTM of 48 h (TTM48) would exhibit better cognitive functions compared to those subjected to standard TTM of 24 h (TTM24) six months post-OHCA. METHODS: A predefined, cognitive post-hoc sub-study was conducted on the multicentre clinical trial: "Target Temperature Management for 48 vs. 24 h and Neurologic Outcome after out-of-hospital cardiac arrest: A Randomised Clinical Trial" (the TTH48 trial). OHCA survivors with perceived good cognitive outcome (CPC score ≤ 2) were invited to a neuropsychological assessment of memory, attention, and executive functions six months post-OHCA. RESULTS: In total, 79 patients were included in the study. Multivariate regression analysis revealed that TTM48 was associated with a significant better performance on three of 13 cognitive tests specific to memory retrieval after adjusting for age at follow-up and time to return of spontaneous circulation. Overall, patients in the TTM24 group were almost three times more likely (RR = 2.9 (95% CI 1.1-7.4)), p = 0.02) to be cognitively impaired. CONCLUSIONS: This study reports an association between the duration of TTM and cognitive outcome. In OHCA survivors with perceived good cognitive outcome (CPC ≤ 2), TTM48 was associated with reduced memory retrieval deficits and lower relative risk of cognitive impairment six months after OHCA compared to standard TTM24. ClinicalTrials.gov (identifier: NCT01689077).

Large inter-rater variability on EEG-reactivity is improved by a novel quantitative method.

OBJECTIVE: To assess inter-rater agreement on EEG-reactivity (EEG-R) in comatose patients and compare it with a quantitative method (QEEG-R). METHODS: Six 30-s stimulation epochs (noxious, visual and auditory) were performed during EEG on 19 neurosurgical and 11 cardiac arrest patients. Six experts analysed EEGs for reactivity using their habitual methods. QEEG-R was defined as present if ≥2/6 epochs were reactive (stimulation/rest power ratio exceeding noise level). Three-months patient outcome was assessed by the Cerebral Performance Category Score (CPC) dichotomized in good (1-2) or poor (3-5). RESULTS: Agreement among experts on overall EEG-R varied from 53% to 83% (κ: 0.05-0.64) and reached 100% (κ: 1) between two QEEG-R calculators. For the experts, absence of EEG-R yielded sensitivities for poor outcome between 40-85% and specificities between 20-90%, for QEEG-R sensitivity was 40% (CI: 23-68%) and specificity 100% (CI: 69-100%). CONCLUSIONS: There is a large inter-rater variation among experts on EEG-R assessment in comatose patients. QEEG-R is a promising objective prognostic parameter with low inter-rater variation and a high specificity for prediction of poor outcome. SIGNIFICANCE: Clinicians should be cautious when using the traditional, qualitative method, in particular in end-of-life decisions. Implementation of the quantitative method in clinical practice may improve reliability of reactivity assessments.

Neuron-specific enolase and S-100b in prolonged targeted temperature management after cardiac arrest: A randomised study.

BACKGROUND: We aimed to investigate the impact of prolonged targeted temperature management (TTM) in cardiac arrest patients on release of serum levels of NSE and S-100b and their prognostic performances. METHODS: This is a substudy of the Targeted Temperature Management for 24 vs 48h trial. NSE and S-100b levels were analysed retrospectively in serum samples collected upon admission, at 24, 48, and 72h after reaching the target temperature of 33±1°C. The primary outcome was biomarker serum concentrations and secondary outcome was the cerebral performance category score after 6 months. RESULTS: 115 patients from two centres were analysed. NSE and S-100b levels did not differ between TTM groups at any single time-point. Poor outcome patients had higher biomarker levels at 24, 48, and 72h: NSE: 9.73 (7.2; 10.9) versus 20.40 (12.7; 27.2), 8.86 (6.6; 9.6) versus 17.47 (11.1; 37.3) and 6.23 (5.3; 8.5) versus 31.05 (12.8; 52.5) respectively and S-100b: 0.09 (0.07; 0.11) versus 0.23 (0.19; 0.39), 0.08 (0.07; 0.09) versus 0.18 (0.15; 0.33) and 0.07 (0.06; 0.08) versus 0.13 (0.09; 0.23). The daily changes in NSE from admission to Day 2 after the cardiac arrest (CA) were also related to the outcome (p=0.003 and p=0.02). The best prediction of outcome was found at 72h for NSE and at 24h as well as 48h for S100b. CONCLUSIONS: No clinically relevant differences were found in the levels of NSE or S-100b between standard and prolonged TTM. Prognostic reliability of NSE and S-100b was unaltered by prolonged TTM.

Prolonged targeted temperature management compromises thrombin generation: A randomised clinical trial.

AIM: To investigate whether prolonged compared with standard duration of targeted temperature management (TTM) compromises coagulation. METHODS: Comatose survivors after out-of-hospital cardiac arrest (n=82) were randomised to standard (24h) or prolonged (48h) duration of TTM at 33±1°C. Blood samples were drawn 22, 46 and 70h after attaining the target temperature. Samples were analysed for rotational thromboelastometry (ROTEM® (EXTEM®, INTEM®, FIBTEM® and HEPTEM®)) and thrombin generation using the Calibrated Automated Thrombogram® assay. RESULTS: With the 22-h sample, we revealed no difference between groups in the ROTEM® and thrombin generation results beside a slightly higher EXTEM® and INTEM® maximum velocity in the prolonged group (p-values≤0.04). With the 46-h sample, ROTEM® showed no differences when using EXTEM®; however, 11% (p<0.01) longer clotting time and 12% (p<0.01) longer time to maximum velocity were evident in the prolonged group than in the standard group when using INTEM®. The prolonged group had reduced thrombin generation compared with the standard group as indicated by 30% longer lag time (p=0.04), 106nM decreased peak concentration (p<0.001), 36% longer time to peak (p=0.01) and 411 nM*minute decreased endogenous thrombin potential (p<0.001). With the 70-h sample, no differences in ROTEM® results were found between groups. However, the prolonged group had reduced thrombin generation indicated by longer lag time, decreased peak concentration and longer time to peak (all p-values≤0.02) compared with the standard group. CONCLUSION: Prolonged TTM in post-cardiac arrest patients impairs thrombin generation. ClinicalTrials.gov identifier: NCT02258360.

The Extent of Myocardial Injury During Prolonged Targeted Temperature Management After Out-of-Hospital Cardiac Arrest.

AIM: The aim of this study is to evaluate the extent of myocardial injury by cardiac biomarkers during prolonged targeted temperature management of 24 hours vs 48 hours after out-of-hospital cardiac arrest. METHODS: This randomized Scandinavian multicenter study compares the extent of myocardial injury quantified by area under the curve (AUC) of cardiac biomarkers during prolonged targeted temperature management at 33°C ± 1°C of 24 hours and 48 hours, respectively. Through a period of 2.5 years, 161 comatose out-of-hospital cardiac arrest patients were randomized to targeted temperature management for 24 hours (n = 77) or 48 hours (n = 84). The AUC was calculated using both high-sensitivity cardiac troponin T (hs-cTnTAUC) and creatine kinase-myocardial band (CK-MBAUC) that were based upon measurements of these biomarkers every 6 hours upon admission until 96 hours after reaching target temperature. RESULTS: The median hs-cTnTAUC of 33,827 ng/L/h (interquartile range [IQR] 11,366-117,690) of targeted temperature management at 24 hours did not differ significantly from that of 28,973 ng/L/h (IQR 10,656-163,655) at 48 hours. In contrast, the median CK-MBAUC of 1829 µg/L/h (IQR 800-6799) during targeted temperature management at 24 hours was significantly lower than that of 2428 µg/L/h (IQR 1163-10,906) within targeted temperature management at 48 hours, P <.05. CONCLUSION: This study of comatose out-of-hospital cardiac arrest survivors showed no difference between the extents of myocardial injury estimated by hs-cTnTAUC of prolonged targeted temperature management of 48 hours vs 24 hours, although the CK-MBAUC was significantly higher during 48 hours vs 24 hours. Hence, it seems unlikely that the duration of targeted temperature management has a beneficial effect on the extent of myocardial injury after out-of-hospital cardiac arrest, and may even have a worsening effect.

Effect of prolonged targeted temperature management on left ventricular myocardial function after out-of-hospital cardiac arrest - A randomised, controlled trial.

AIM: To evaluate post-cardiac arrest myocardial dysfunction during prolonged targeted temperature management (TTM) compared with standard TTM in comatose out-of-hospital cardiac arrest (OHCA) survivors. METHODS: A randomised, controlled trial comparing myocardial function after TTM at 33 ±1°C for 48h compared with 24h. A total of 105 OHCA patients were computer-randomised to 24h (n=50) or 48h (n=55) of TTM. Transthoracic echocardiography was performed after 24h, 48h and 72h. Echocardiographic parameters were evaluated by an investigator who was blinded to randomisation. The primary endpoint was peak systolic mitral annular velocity (S) measured as the difference in the period from 24h to 72h. The model was adjusted for age, primary rhythm and heart rate. The secondary outcomes were global peak longitudinal strain, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE) and the diastolic measures e' and E/e'. RESULTS: The mean difference of S' was significantly increased in the 48h group compared with the 24h group: -1.14cm/s (-1.83; -0.45), p=0.001. This difference was consistent after adjusting the data (p=0.008). However, there were no significant changes between the study groups with respect to the adjusted secondary outcomes of global peak longitudinal strain (p=0.07), LVEF (p=0.31), TAPSE (p=0.91), e' (p=0.26) and E/e' (p=0.18). CONCLUSION: Prolonged TTM at 33°C of 48h compared with 24h in comatose OHCA survivors may improve the recovery of post-cardiac arrest left myocardial dysfunction demonstrated by the echocardiographic outcome, S'. ClinicalTrials.gov identifier: NCT02066753.

Time-differentiated target temperature management after out-of-hospital cardiac arrest: a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial.

BACKGROUND: The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome. METHODS: The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients. DISCUSSION: This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients. TRIAL REGISTRATION: NCT01689077.