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.

Bacterial findings in patients referred to hospital for the treatment of acute tonsillitis with or without peritonsillar phlegmon.

BACKGROUND: The vast majority of patients with acute tonsillitis (AT) are managed in general practice. However, occasionally patients are referred to hospital for specialized management because of aggravated symptoms and/or findings suggestive of peritonsillar involvement. No prospective studies have been conducted aiming to investigate the prevalent and significant microorganisms in this highly selected group of patients. We aimed to describe the microbiological findings of acute tonsillitis with or without peritonsillar phlegmon (PP) in patients referred for hospital treatment and to point out potential pathogens using the following principles to suggest pathogenic significance: (1) higher prevalence in patients compared to healthy controls, (2) higher abundance in patients compared to controls, and (3) higher prevalence at time of infection compared to time of follow up. METHODS: Meticulous and comprehensive cultures were performed on tonsillar swabs from 64 patients with AT with (n = 25) or without (n = 39) PP and 55 healthy controls, who were prospectively enrolled at two Danish Ear-Nose-Throat Departments between June 2016 and December 2019. RESULTS: Streptococcus pyogenes was significantly more prevalent in patients (27%) compared to controls (4%) (p < 0.001). Higher abundance was found in patients compared to controls for Fusobacterium necrophorum (mean 2.4 vs. 1.4, p = 0.017) and S. pyogenes (mean 3.1 vs. 2.0, p = 0.045) in semi-quantitative cultures. S. pyogenes, Streptococcus dysgalactiae, and Prevotella species were significantly more prevalent at time of infection compared to follow up (p = 0.016, p = 0.016, and p = 0.039, respectively). A number of species were detected significantly less frequently in patients compared to controls and the mean number of species was significantly lower in patients compared to controls (6.5 vs. 8.3, p < 0.001). CONCLUSIONS: Disregarding Prevotella spp. because of the prevalence in healthy controls (100%), our findings suggest that S. pyogenes, F. necrophorum, and S. dysgalactiae are significant pathogens in severe AT with or without PP. In addition, infections were associated with reduced diversity (dysbacteriosis). TRIAL REGISTRATION: The study is registered in the ClinicalTrials.gov protocol database (# 52,683). The study was approved by the Ethical Committee at Aarhus County (# 1-10-72-71-16) and by the Danish Data Protection Agency (# 1-16-02-65-16).

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.

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.

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.

Electrolyte profiles with induced hypothermia: A sub study of a clinical trial evaluating the duration of hypothermia after cardiac arrest.

BACKGROUND: Electrolyte disturbances can result from targeted temperature treatment (TTM) in out-of-hospital cardiac arrest (OHCA) patients. This study explores electrolyte changes in blood and urine in OHCA patients treated with TTM. METHODS: This is a sub-study of the TTH48 trial, with the inclusion of 310 unconscious OHCA patients treated with TTM at 33°C for 24 or 48 h. Over a three-day period, serum concentrations were obtained on sodium potassium, chloride, ionized calcium, magnesium and phosphate, as were results from a 24-h diuresis and urine electrolyte concentration and excretion. Changes over time were analysed with a mixed-model multivariate analysis of variance with repeated measurements. RESULTS: On admission, mean ± SD sodium concentration was 138 ± 3.5 mmol/l, which increased slightly but significantly (p < .05) during the first 24 h. Magnesium concentration stayed within the reference interval. Median ionized calcium concentration increased from 1.11 (IQR 1.1-1.2) mmol/l during the first 24 h (p < .05), whereas median phosphate concentration dropped to 1.02 (IQR 0.8-1.2) mmol/l (p < .05) and stayed low. During rewarming, potassium concentrations increased, and magnesium and ionizes calcium concentration decreased (p < .05). Median 24-h diuresis results on days one and two were 2198 and 2048 ml respectively, and the electrolyte excretion mostly stayed low in the reference interval. CONCLUSIONS: Electrolytes mostly remained within the reference interval. A temporal change occurred in potassium, magnesium and calcium concentrations with TTM's different phases. No hypothermia effect on diuresis was detected, and urine excretion of electrolytes mostly stayed low.

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.

In-person versus video instruction of patients with sleep apnoea in the use of continuous positive airway pressure (CPAP).

INTRODUCTION: Instructing newly diagnosed sleep apnoea patients in the use of continuous positive airway pressure (CPAP) machines is time consuming for healthcare workers and patients alike. Our aim was to test the feasibility of video instruction as an alternative to physical attendance in the clinic. METHODS: In this randomised controlled trial, we enrolled 120 patients who were randomised to either classic instruction by a nurse or video instruction at home. Both patients and doctors answered questionnaires at the time of inclusion. Follow-up was 1-3 months. RESULTS: No significant difference was recorded between the two groups on any measured parameter. CONCLUSIONS: Video instruction is feasible and should be considered as an alternative to physical attendance for the CPAP start-up. FUNDING: none. TRIAL REGISTRATION: clinicaltrials.gov (NCT number 15022020).

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.

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.

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.

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.

Cold fluids for induction of targeted temperature management: A sub-study of the TTH48 trial.

BACKGROUND: Pre-intensive care unit (ICU) induction of targeted temperature management (TTM) with cold intravenous (i.v.) fluids does not appear to improve outcomes after in out-of-hospital cardiac arrest (OHCA). We hypothesized that this may be due to ineffective cooling and side effects. METHODS: A post hoc analysis of a sub-group of patients (n = 352) in the TTH48 trial (NCT01689077) who received or did not receive pre-ICU cooling using cold i.v. fluids. Data collection included patient characteristics, cardiac arrest factors, cooling methods, side effects and continuous core temperature measurements. The primary endpoint was the time to target temperature (TTT, <34 °C), and the secondary endpoints included the incidence of circulatory side effects, abnormal electrolyte levels and hypoxia within the first 24 h of ICU care. A difference of 1 h in the TTT was determined as clinically significant a priori. RESULTS: Of 352 patients included in the present analysis, 110 received pre-ICU cold fluids. The median time to the return of spontaneous circulation (ROSC) and TTT in the pre-ICU cold fluids group was longer than that of the group that did not receive pre-ICU cold fluids (318 vs. 281 min, p < 0.01). In a linear regression model including the treatment centre, body mass index (BMI), chronic heart failure, diabetes mellitus and time to ROSC, the use of pre-ICU cold i.v. fluids was not associated with a shorter time to the target temperature (standardized beta coefficient: 0.06, 95% CI for B -49 and 16, p  =  0.32). According to the receipt or not of pre-ICU cold i.v. fluids, there was no difference in the proportion of patients with hypoxia on ICU admission (1.8% vs. 3.3%, p =  0.43) or the proportion of patients with electrolyte abnormalities (hyponatremia: 1.8% vs. 2.9% p = 0.54; hypokalaemia: 1.8% vs. 4.5%, p =  0.20). Furthermore, there was no difference in hospital mortality between the groups. CONCLUSIONS: The initiation of TTM with cold i.v. fluids before ICU arrival did not decrease the TTT. We detected no significant between-group difference in mortality or the incidence of side effects according to the administration or not of pre-ICU cold i.v fluids.

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.

Hypothermic to ischemic ratio and mortality in post-cardiac arrest patients.

BACKGROUND: We studied the associations between ischemia and hypothermia duration, that is, the hypothermic to ischemic ratio (H/I ratio), with mortality in patients included in a trial on two durations of targeted temperature management (TTM) at 33°C. METHODS: The TTH48 (NCT01689077) trial compared 24 and 48 hours of TTM in patients after cardiac arrest. We calculated the hypothermia time from return of spontaneous circulation (ROSC) until the patient reached 37°C after TTM and the ischemic time from CA to ROSC. We compared continuous variables with the Mann-Whitney U test. Using COX regression, we studied the independent association of the logarithmically transformed H/I ratio and time to death as well as interaction between time to ROSC, hypothermia duration, and intervention group. We visualized the predictive ability of variables with receiver operating characteristic curve analysis. RESULTS: Of the 338 patients, 237 (70%) survived for 6 months. The H/I ratio was 155 (IQR 111-238) in survivors and 114 (IQR 80-169) in non-survivors (P < .001). In a Cox regression model including factors associated with outcome in univariate analysis, the logarithmically transformed H/I ratio was a significant predictor of outcome (hazard ratio 0.52 (0.37-0.72, P = .001)). After removing an outlier, we found no interaction between time to ROSC and intervention group (P = .55) or hypothermia duration in quartiles (P = .07) with mortality. There was no significant difference in the area under the curve (AUC) between time to ROSC and H/I ratio (ΔAUC 0.03 95% CI -0.006-0.07, P = .10). CONCLUSIONS: We did not find any consistent evidence of a modification of the effect of TTM based on ischemia duration.

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.