Neurofilament Light Chain and Glial Fibrillary Acidic Protein as early prognostic biomarkers after out-of-hospital cardiac arrest.

AIMS: Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) are proteins released into the bloodstream upon hypoxic brain injury. We evaluated the biokinetics and examined the prognostic performance of serum NfL and GFAP in comatose out-of-hospital cardiac arrest (OHCA) patients. Furthermore, we compared the prognostic performance to that of serum Neuron Specific Enolase (NSE). METHODS: This is a sub-study of the "Targeted temperature management for 48 vs 24 hours" (NCT01689077) trial. NfL and GFAP serum values from 82 patients were examined in blood samples collected at 24, 48 and 72 hours (h) after reaching target temperature of 33 ± 1 °C. This temperature was reached within a median of 281-320 minutes after intensive care unit admission. GFAP was analysed at 48 and 72 h. The neuroprognostic performance of NfL and GFAP was evaluated after 6 months follow-up. RESULTS: NfL and GFAP values were significantly higher in patients with a poor outcome (Cerebral Performance Category (CPC) score 3-5) vs. good outcome (CPC 1-2). NfL 24 h: 1371.5 (462.0; 2125.1) vs. 24.8 (14.0; 61.6). GFAP 48 h: 1285.3 (843.9; 2236.7) vs. 361.2 (200.4; 665.6) (both p < 0.001). Both biomarkers were promising markers of poor functional outcome at 24 and 48 h respectively: NfL 24 h: AUROC 0.95 (95% CI: 0.91-1.00). GFAP 48 h: AUROC 0.88 (95% CI: 0.81-0.96). NfL and GFAP both predicted outcome better than NSE at 48 h (both p < 0.01). At 72 h NfL but not GFAP outperformed NSE (p = 0.01). CONCLUSION: Serum NfL and GFAP may be strong biomarkers of poor functional outcome after OHCA from an early timepoint.

Bleeding patients on extracorporeal membrane oxygenation have reduced platelet aggregation and plasma fibrinogen: a longitudinal observational study.

This study investigated changes in coagulation and associations with occurrence of bleeding and thrombosis during extracorporeal membrane oxygenation (ECMO) therapy. The study included 100 adult ECMO-patients. Standard coagulation parameters, platelet aggregation and thromboelastometry (ROTEM®) were compared with healthy controls. Data on bleeding and thrombosis were collected until recovery or death. Mortality data were collected 30 days after weaning from ECMO. During ECMO therapy, 53 patients experienced at least one moderate or major bleed. Among these, 42 (79%) patients experienced the first bleeding on day 1 or 2. Platelet aggregation and ROTEM® revealed a hypocoagulable state in ECMO patients when compared with healthy controls. Patients bleeding on day 1 or 2, had lower platelet count (p = 0.04), poorer platelet aggregation and lower levels of fibrinogen (p < 0.01) than patients not bleeding on day 1 or 2. Further, ROTEM® clot propagation was reduced in bleeding patients (p < 0.001). Mortality was higher among bleeding patients than patients not bleeding on day 1 or 2 (67% versus 34%, p < 0.01). Congruity existed between ROTEM® measurements and standard coagulation assays, but plasma fibrinogen had a stronger association with bleeding than ROTEM® measurements. The present study does not support ROTEM® analysis as a routine part of coagulation monitoring during ECMO therapy.

Individualised perioperative blood pressure and fluid therapy in oesophagectomy ­ study protocol for a randomised clinical trial

INTRODUCTION: Oesophagectomy is the mainstay of curative treatment for oesophageal cancer, but it is associated with a high risk of major complications. Goal-directed fluid therapy and individualised blood pressure management may prevent complications after surgery. Extending goal-directed fluid therapy after surgery and applying an individual blood pressure target may have substantial benefit in oesophagectomy. This is a protocol for a clinical trial implementing a novel haemodynamic protocol from the start of anaesthesia to the next day with the patient's own night-time blood pressure as the lower threshold. METHODS: This is a single-centre, single-blind, randomised, clinical trial. Oesophagectomy patients are randomised 1:1 for either perioperative haemodynamic management according to a goal-directed fluid therapy protocol with an individual target blood pressure or for standard care. The primary endpoint is the total burden of morbidity and mortality assessed by the Comprehensive Complication Index 30 days after surgery. Secondary endpoints are complications, reoperations, fluid and vasopressor dosage and quality of life at 90 days after surgery. CONCLUSIONS: The results from this trial provide an objective and easy-to-follow algorithm for fluid administration, which may improve patient-centred outcomes in oesophagectomy patients. FUNDING: The trial is supported by Aarhus University (1,293,400 DKK) and the Novo Nordisk Foundation (625,200 DKK). TRIAL REGISTRATION: EudraCT number: 2021-002816-30.

Fibrinolysis in Cardiac Arrest Patients Treated with Hypothermia.

Hypothermia affects coagulation, but the effect of hypothermia on fibrinolysis is not clarified. Imbalance in the fibrinolytic system may lead to increased risk of bleeding or thrombosis. Our aim was to investigate if resuscitated cardiac arrest patients treated with hypothermia had an unbalanced fibrinolysis. A prospective cohort study, including 82 patients were treated with hypothermia at 33°C ± 1°C after out-of-hospital cardiac arrest. Blood samples were collected at 24 hours (hypothermia) and at 72 hours (normothermia). Samples were analyzed for fibrin D-dimer, tissue plasminogen activator (tPA), plasminogen, plasminogen activator Inhibitor-1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and an in-house dynamic fibrin clot formation and lysis assay.Compared with normothermia, hypothermia significantly increased plasminogen activity (mean difference = 10.4%, 95% confidence interval [CI] 7.9-12.9), p < 0.001), PAI-1 levels (mean difference = 275 ng/mL, 95% CI 203-348, p < 0.001), and tPA levels (mean difference = 1.0 ng/mL, 95% CI 0.2-1.7, p = 0.01). No differences between hypothermia and normothermia were found in TAFI activity (p = 0.59) or in the fibrin D-dimer levels (p = 0.08). The fibrin clot lysis curves showed three different patterns: normal-, flat-, or resistant clot lysis curve. At hypothermia 45 (55%) patients had a resistant clot lysis curve and 33 (44%) patients had a resistant clot lysis curve at normothermia (p = 0.047). Comatose, resuscitated, cardiac arrest patients treated with hypothermia express an inhibited fibrinolysis even after rewarming. This could potentially increase the thromboembolic risk. ClinicalTrials.gov ID: NCT02258360.

Kinetics of 2 different high-sensitive troponins during targeted temperature management in out-of-hospital cardiac arrest patients with acute myocardial infarction: a post hoc sub-study of a randomised clinical trial.

INTRODUCTION: Short term hypothermia has been suggested to have cardio protective properties in acute myocardial infarction (AMI) by reducing infarct size as assessed by troponins. There are limited data on the kinetics of these biomarkers in comatose out-of-hospital cardiac arrest (OHCA) patients, with and without AMI, undergoing targeted temperature management (TTM) in the ICU. PURPOSE: The aim of this post hoc analyses was to evaluate and compare the kinetics of two high-sensitivity cardiac troponins in OHCA survivors, with and without acute myocardial infarction (AMI), during TTM of different durations [24 h (standard) vs. 48 h (prolonged)]. METHODS: In a sub-cohort (n = 114) of the international, multicentre, randomized controlled study "TTH48" we measured high-sensitive troponin T (hs-cTnT), high-sensitive troponin I (hs-cTnI) and CK-MB at the following time points: Arrival, 24 h, 48 h and 72 h from reaching the target temperature range of 33 ± 1 °C. All patients diagnosed with an AMI at the immediate coronary angiogram (CAG)-18 in the 24-h group and 25 in the 48-h group-underwent PCI with stent implantation. There were no stent thromboses. RESULTS: Both the hs-cTnT and hs-cTnI changes over time were highly influenced by the cause of OHCA (AMI vs. non-AMI). In contrast to non-AMI patients, both troponins remained elevated at 72 h in AMI patients. There was no difference between the two time-differentiated TTM groups in the kinetics for the two troponins. CONCLUSION: In comatose OHCA survivors with an aetiology of AMI levels of both hs-cTnI and hs-cTnT remained elevated for 72 h, which is in contrast to the well-described kinetic profile of troponins in normotherm AMI patients. There was no difference in kinetic profile between the two high sensitive assays. Different duration of TTM did not influence the kinetics of the troponins. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01689077, 20/09/2012.

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.

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.

Quality of targeted temperature management and outcome of out-of-hospital cardiac arrest patients: A post hoc analysis of the TTH48 study.

BACKGROUND: No data are available on the quality of targeted temperature management (TTM) provided to out-of-hospital cardiac arrest (OHCA) patients and its association with outcome. METHODS: Post hoc analysis of the TTH48 study (NCT01689077), which compared the effects of prolonged TTM at 33 °C for 48 h to standard 24-h TTM on neurologic outcome. Admission temperature, speed of cooling, rewarming rates, precision (i.e. temperature variability), overcooling and overshooting as post-cooling fever (i.e. >38.0 °C) were collected. A specific score, ranging from 1 to 9, was computed to define the "quality of TTM". RESULTS: On a total of 352 patients, most had a moderate quality of TTM (n = 217; 62% - score 4-6), while 80 (23%) patients had a low quality of TTM (score 1-3) and only 52 (16%) a high quality of TTM (score 7-9). The proportion of patients with unfavorable neurological outcome (UO; Cerebral Performance Category of 3-5 at 6 months) was similar between the different quality of TTM groups (p = 0.90). Although a shorter time from arrest to target temperature and a lower proportion of time outside the target ranges in the TTM 48-h than in the TTM 24-h group, quality of TTM was similar between groups. Also, the proportion of patients with UO was similar between the different quality of TTM groups when TTM 48-h and TTM 24-h were compared. CONCLUSIONS: In this study, high quality of TTM was provided to a small proportion of patients. However, quality of TTM was not associated with patients' outcome.

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.

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.

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.

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.

Association Between ICU-Acquired Hypernatremia and In-Hospital Mortality: Data From the Medical Information Mart for Intensive Care III and the Electronic ICU Collaborative Research Database.

OBJECTIVES: Describe the relationship between ICU-acquired hypernatremia and in-hospital mortality and investigate the optimal hypernatremia correction rate. DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: Observational study including two individual ICU cohorts. We used the Medical Information Mart for Intensive Care III v. 1.4 database consists of all ICU patients admitted to the Beth Israel Deaconess Medical Center in Boston from 2001 to 2012 (n = 46,476). The electronic ICU v. 2.0 database consists of all ICU patients admitted to 208 distinct hospitals across the United States from 2014 to 2015 (n = 200,859). We included all adult patients admitted to an ICU with two consecutive sodium samples within normal range (135-145 mmol/L) and without two consecutive hyponatremic samples (< 135 mmol/L) during the ICU stay. RESULTS: Of 23,445 patients identified in Medical Information Mart for Intensive Care III, 9% (n = 2,172) developed hypernatremia during their ICU stay. In electronic ICU, 88,160 patients were identified and 7% (n = 5,790) developed hypernatremia. In both cohorts, patients with hypernatremia had a higher mortality (Medical Information Mart for Intensive Care III: 20% vs 42%; p < 0.01 and electronic ICU: 6% vs 22%; p < 0.01), with hypernatremia increasing the risk of in-hospital mortality (Medical Information Mart for Intensive Care III: odds ratio, 1.15; 95% CI, 1.13-1.17 and electronic ICU: odds ratio, 1.11; 95% CI, 1.10-1.12) and over time using a Cox regression. Rapid sodium correction rate (> 0.5 mmol/L/hr) was associated with an increased in-hospital mortality in both cohorts (Medical Information Mart for Intensive Care III: odds ratio, 1.08; 95% CI, 1.03-1.13 and electronic ICU: odds ratio, 1.10; 95% CI, 1.06-1.13). In the electronic ICU cohort, rapid correction rates were associated with a significant difference in in-hospital mortality, but there was no statistically significant association in the Medical Information Mart for Intensive Care III cohort. CONCLUSIONS: ICU-acquired hypernatremia is associated with increased in-hospital mortality. Furthermore, a rapid sodium correction rates may be harmful. This suggests it is important to both prevent ICU-acquired hypernatremia and to avoid rapid correction rates if a patient becomes hypernatremic.

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.

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 complement lectin pathway protein MAp19 and out-of-hospital cardiac arrest: Insights from two randomized clinical trials.

AIM: Activation of the complement system is known to be a potent inducer of systemic inflammation, which is an important component of post-cardiac arrest syndrome. Mannan-binding-lectin associated protein of 19 kDa (MAp19) is suggested to be a regulatory component of the lectin pathway of complement activation. The aims of this study were to describe serial levels of MAp19 protein in comatose survivors of out-of-hospital cardiac arrest (OHCA), to evaluate the effect of two different regimes of targeted temperature management and to investigate the possible association between levels of MAp19 and mortality. METHODS: In this post-hoc study, we analysed data from two large randomized controlled studies: 'Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest' (TTM) and 'Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest' (TTH). We measured serial levels of MAp19 in 240 patients within 72 h after OHCA and in 82 healthy controls. The effect of targeted temperature management on MAp19 levels was analysed according to temperature allocation in main trials. RESULTS: MAp19 levels were significantly lower in OHCA patients within 48 h after OHCA (p-values <0.001) compared with healthy controls. A target temperature at 33°C compared with 36°C for 24 h was associated with significantly lower levels of MAp19 (-57 ng/mL (95% confidence interval (CI): -97 to -16 mg/mL), p=0.006). Target temperature at 33°C for 48 h compared with 24 h was not associated with a difference in MAp19 levels (-31 ng/mL (95% CI: -120 to 60 mg/mL), p=0.57). Low MAp19 levels at admission were associated with higher 30-day mortality (12% vs. 38%, plog-rank =0.0008), also in adjusted analysis (two-fold higher, hazard ratio =0.48 (95% CI: 0.31 to 0.75), p=0.001). Analysis of MAp19 levels at 24-72 h showed they were not associated with 30-day mortality. CONCLUSION: Survivors after OHCA have lower levels of MAp19 protein compared with healthy controls. A targeted temperature management at 33°C compared with 36°C was associated with significantly lower MAp19 levels, whereas target temperature at 33°C for 48 h compared with 24 h did not influence MAp19 protein levels. Low MAp19 levels at admission were independently associated with increased mortality.

Platelet Function During Extracorporeal Membrane Oxygenation in Adult Patients.

Objective: Hemorrhagic and thromboembolic complications are common during support with extracorporeal membrane oxygenation (ECMO). As platelets play a pivotal role in hemostasis, we aimed to clarify how ECMO support affects platelet function. Methods: We included 33 adult patients undergoing ECMO support at a tertiary ECMO referral center at Aarhus University Hospital, Denmark. Blood samples were collected on the first morning following ECMO initiation, and subsequently every morning until the 7th (±1) day. Platelet aggregation was evaluated by whole blood impedance aggregometry (Multiplate® Analyzer) using adenosine diphosphate (ADPtest), arachidonic acid (ASPItest), and thrombin-receptor-agonist-peptide-6 (TRAPtest) as agonists. A new model was applied, taking platelet count into consideration in interpretation of impedance aggregometry analyses. On the 1st and 3rd day, platelet activation was assessed by flow cytometry (Navios) using collagen-related peptide, ADP, TRAP, and arachidonic acid as agonists. Results: Blood samples from all 33 patients were analyzed on day 1 of ECMO support; 24 patients were still receiving ECMO and analyzed on day 3; 12 patients were analyzed on day 7 (±1). After ECMO initiation, platelet counts decreased significantly (p < 0.002) and remained low during ECMO support. ECMO patients demonstrated significantly reduced platelet aggregation on day 1 compared with healthy controls (all p < 0.001). However, when taking platelet count into consideration, platelet aggregation relative to platelet count did not differ from healthy controls. Flow cytometry analyses demonstrated impaired platelet activation in ECMO patients on day 1 compared with healthy controls (all p < 0.03). No substantial difference was found in platelet activation from day 1 to day 3 on ECMO support. Conclusions: Employing impedance aggregometry and flow cytometry, we found both impaired platelet aggregation and decreased platelet activation on day 1 of ECMO support compared with healthy controls. However, platelet aggregation was not impaired, when interpreted relative to the low platelet counts. Furthermore, levels of bound fibrinogen, on the surface of activated platelets in ECMO patients, were higher than in healthy controls. Together, these findings suggestively oppose that platelets are universally impaired during ECMO support. No marked difference in activation from day 1 to day 3 was seen during ECMO support.

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).