Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Veno-arterial CO2 difference and lactate for prediction of early mortality after cardiac arrest.

Patients admitted to intensive care after cardiac arrest are at risk of circulatory shock and early mortality due to cardiovascular failure. The aim of this study was to evaluate the ability of the veno-arterial pCO2 difference (∆pCO2 ; central venous CO2 - arterial CO2 ) and lactate to predict early mortality in postcardiac arrest patients. This was a pre-planned prospective observational sub-study of the target temperature management 2 trial. The sub-study patients were included at five Swedish sites. Repeated measurements of ∆pCO2 and lactate were conducted at 4, 8, 12, 16, 24, 48, and 72 h after randomization. We assessed the association between each marker and 96-h mortality and their prognostic value for 96-h mortality. One hundred sixty-three patients were included in the analysis. Mortality at 96 h was 17%. During the initial 24 h, there was no difference in ∆pCO2 levels between 96-h survivors and non-survivors. ∆pCO2 measured at 4 h was associated with an increased risk of death within 96 h (adjusted odds ratio: 1.15; 95% confidence interval [CI]: 1.02-1.29; p = .018). Lactate levels were associated with poor outcome over multiple measurements. The area under the receiving operating curve to predict death within 96 h was 0.59 (95% CI: 0.48-0.74) and 0.82 (95% CI: 0.72-0.92) for ∆pCO2 and lactate, respectively. Our results do not support the use of ∆pCO2 to identify patients with early mortality in the postresuscitation phase. In contrast, non-survivors demonstrated higher lactate levels in the initial phase and lactate identified patients with early mortality with moderate accuracy.

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial.

BACKGROUND: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA. METHODS: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups. RESULTS: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis. CONCLUSIONS: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016.

Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial.

BACKGROUND: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest. METHODS: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score. RESULTS: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001. CONCLUSION: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure. TRIAL REGISTRATION: Clinical Trials, NCT01020916. Registered November 26, 2009.

Bedside interpretation of simplified continuous EEG after cardiac arrest.

BACKGROUND: Continuous EEG-monitoring (cEEG) in the ICU is recommended to assess prognosis and detect seizures after cardiac arrest but implementation is often limited by the lack of EEG-technicians and experts. The aim of the study was to assess ICU physicians ability to perform preliminary interpretations of a simplified cEEG in the post cardiac arrest setting. METHODS: Five ICU physicians received training in interpretation of simplified cEEG - total training duration 1 day. The ICU physicians then interpreted 71 simplified cEEG recordings from 37 comatose survivors of cardiac arrest. The cEEG included amplitude-integrated EEG trends and two channels with original EEG-signals. Basic EEG background patterns and presence of epileptiform discharges or seizure activity were assessed on 5-grade rank-ordered scales based on standardized EEG terminology. An EEG-expert was used as reference. RESULTS: There was substantial agreement (κ 0.69) for EEG background patterns and moderate agreement (κ 0.43) for epileptiform discharges between ICU physicians and the EEG-expert. Sensitivity for detecting seizure activity by ICU physicians was limited (50%), but with high specificity (87%). CONCLUSIONS: After cardiac arrest, preliminary bedside interpretations of simplified cEEGs by trained ICU physicians may allow earlier detection of clinically relevant cEEG changes, prompting changes in patient management as well as additional evaluation by an EEG-expert. This strategy requires awareness of limitations of both the simplified electrode montage and the cEEG interpretations performed by ICU physicians. cEEG evaluation by an expert should not be delayed.

Regional Brain Net Water Uptake in Computed Tomography after Cardiac Arrest - A Novel Biomarker for Neuroprognostication.

BACKGROUND: Selective water uptake by neurons and glial cells and subsequent brain tissue oedema are key pathophysiological processes of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA). Although brain computed tomography (CT) is widely used to assess the severity of HIE, changes of brain radiodensity over time have not been investigated. These could be used to quantify regional brain net water uptake (NWU), a potential prognostic biomarker. METHODS: We conducted an observational prognostic accuracy study including a derivation (single center cardiac arrest registry) and a validation (international multicenter TTM2 trial) cohort. Early (<6 h) and follow-up (>24 h) head CTs of CA patients were used to determine regional NWU for grey and white matter regions after co-registration with a brain atlas. Neurological outcome was dichotomized as good versus poor using the Cerebral Performance Category Scale (CPC) in the derivation cohort and Modified Rankin Scale (mRS) in the validation cohort. RESULTS: We included 115 patients (81 derivation, 34 validation) with out-of-hospital (OHCA) and in-hospital cardiac arrest (IHCA). Regional brain water content remained unchanged in patients with good outcome. In patients with poor neurological outcome, we found considerable regional water uptake with the strongest effect in the basal ganglia. NWU >8% in the putamen and caudate nucleus predicted poor outcome with 100% specificity (95%-CI: 86-100%) and 43% (moderate) sensitivity (95%-CI: 31-56%). CONCLUSION: This pilot study indicates that NWU derived from serial head CTs is a promising novel biomarker for outcome prediction after CA. NWU >8% in basal ganglia grey matter regions predicted poor outcome while absence of NWU indicated good outcome. NWU and follow-up CTs should be investigated in larger, prospective trials with standardized CT acquisition protocols.

Standardised and automated assessment of head computed tomography reliably predicts poor functional outcome after cardiac arrest: a prospective multicentre study.

PURPOSE: Application of standardised and automated assessments of head computed tomography (CT) for neuroprognostication after out-of-hospital cardiac arrest. METHODS: Prospective, international, multicentre, observational study within the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Routine CTs from adult unconscious patients obtained > 48 h ≤ 7 days post-arrest were assessed qualitatively and quantitatively by seven international raters blinded to clinical information using a pre-published protocol. Grey-white-matter ratio (GWR) was calculated from four (GWR-4) and eight (GWR-8) regions of interest manually placed at the basal ganglia level. Additionally, GWR was obtained using an automated atlas-based approach. Prognostic accuracies for prediction of poor functional outcome (modified Rankin Scale 4-6) for the qualitative assessment and for the pre-defined GWR cutoff < 1.10 were calculated. RESULTS: 140 unconscious patients were included; median age was 68 years (interquartile range [IQR] 59-76), 76% were male, and 75% had poor outcome. Standardised qualitative assessment and all GWR models predicted poor outcome with 100% specificity (95% confidence interval [CI] 90-100). Sensitivity in median was 37% for the standardised qualitative assessment, 39% for GWR-8, 30% for GWR-4 and 41% for automated GWR. GWR-8 was superior to GWR-4 regarding prognostic accuracies, intra- and interrater agreement. Overall prognostic accuracy for automated GWR (area under the curve [AUC] 0.84, 95% CI 0.77-0.91) did not significantly differ from manually obtained GWR. CONCLUSION: Standardised qualitative and quantitative assessments of CT are reliable and feasible methods to predict poor functional outcome after cardiac arrest. Automated GWR has the potential to make CT quantification for neuroprognostication accessible to all centres treating cardiac arrest patients.

Hypothermia versus normothermia after out-of-hospital cardiac arrest; the effect on post-intervention serum concentrations of sedatives and analgesics and time to awakening.

BACKGROUND: This study investigated the association of two levels of targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) with administered doses of sedative and analgesic drugs, serum concentrations, and the effect on time to awakening. METHODS: This substudy of the TTM2-trial was conducted at three centers in Sweden, with patients randomized to either hypothermia or normothermia. Deep sedation was mandatory during the 40-hour intervention. Blood samples were collected at the end of TTM and end of protocolized fever prevention (72 hours). Samples were analysed for concentrations of propofol, midazolam, clonidine, dexmedetomidine, morphine, oxycodone, ketamine and esketamine. Cumulative doses of administered sedative and analgesic drugs were recorded. RESULTS: Seventy-one patients were alive at 40 hours and had received the TTM-intervention according to protocol. 33 patients were treated at hypothermia and 38 at normothermia. There were no differences between cumulative doses and concentration and of sedatives/analgesics between the intervention groups at any timepoint. Time until awakening was 53 hours in the hypothermia group compared to 46 hours in the normothermia group (p = 0.09). CONCLUSION: This study of OHCA patients treated at normothermia versus hypothermia found no significant differences in dosing or concentration of sedatives or analgesic drugs in blood samples drawn at the end of the TTM intervention, or at end of protocolized fever prevention, nor the time to awakening.

Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock.

INTRODUCTION: The diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock. METHODS: We studied a prospective, observational cohort of 51 patients with shock admitted to a tertiary ICU. EVLW was measured within 6 hours of ICU admission and indexed to actual body weight (EVLW/ABW), predicted body weight (EVLW/PBW) and pulmonary blood volume (EVLW/PBV). The relationship of these indices to the diagnosis and severity of lung injury and ICU mortality were studied. Positive and negative likelihood ratios, pre- and posttest odds for diagnosis of lung injury and mortality were calculated. RESULTS: All EVLW indices were higher among patients with lung injury and significantly correlated with respiratory parameters. Furthermore, all EVLW indices were significantly higher in nonsurvivors. The use of EVLW improves the posttest OR for the diagnosis of ALI, acute respiratory distress syndrome (ARDS) and severe lung injury (sLI) by up to eightfold. Combining increased EVLW and a diagnosis of ALI, ARDS or sLI increases the posttest odds of ICU mortality. EVLW/ABW and EVLW/PBV demonstrated the best diagnostic performance in this population. CONCLUSIONS: EVLW was associated with degree of lung injury and mortality, regardless of the index used, confirming that it may be used as a bedside indicator of disease severity. The use of EVLW as a bedside test conferred added diagnostic value for the identification of patients with lung injury.

High-sensitive cardiac Troponin T is superior to echocardiography in predicting 1-year mortality in patients with SIRS and shock in intensive care.

BACKGROUND: Left ventricular (LV) dysfunction is well documented in the critically ill. We assessed 1-year mortality in relation to cardiac biomarkers and LV function parameters by echocardiography in patients with shock. METHODS: A prospective, observational, cohort study of 49 patients. B-natriuretic peptide (BNP), high-sensitive troponin T (hsTNT) and transthoracic echocardiography (TTE) were assessed within 12 h of study inclusion. LV systolic function was measured by ejection fraction (LVEF), mean atrioventricular plane displacement (AVPDm), peak systolic tissue Doppler velocity imaging (TDIs) and velocity time integral in the LV outflow tract (LVOT VTI). LV diastolic function was evaluated by transmitral pulsed Doppler (E, A, E/A, E-deceleration time), tissue Doppler indices (é, á, E/é) and left atrial volume (La volume). APACHE II (Acute Physiology and Chronic Health Evaluation) and SOFA (Sequential Organ Failure Assessment) scores were calculated. RESULTS: hsTNT was significantly higher in non-survivors than in survivors (60 [17.0-99.5] vs 168 [89.8-358] ng/l, p = 0.003). Other univariate predictors of mortality were APACHE II (p = 0.009), E/é (p = 0.023), SOFA (p = 0.024) and age (p = 0.031). Survivors and non-survivors did not differ regarding BNP (p = 0.26) or any LV systolic function parameter (LVEF p = 0.87, AVPDm p = 0.087, TDIs p = 0.93, LVOT VTI p = 0.18). Multivariable logistic regression analysis identified hsTNT (p = 0.010) as the only independent predictor of 1-year mortality; adjusted odds ratio 2.0 (95% CI 1.2- 3.5). CONCLUSIONS: hsTNT was the only independent predictor of 1-year mortality in patients with shock. Neither BNP nor echocardiographic parameters had an independent prognostic value. Further studies are needed to establish the clinical significance of elevated hsTNT in patients in shock.

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest.

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006-2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1-2) versus poor (CPC 3-5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46-0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.

Prognostic accuracy of head computed tomography for prediction of functional outcome after out-of-hospital cardiac arrest: Rationale and design of the prospective TTM2-CT-substudy.

Background: Head computed tomography (CT) is a guideline recommended method to predict functional outcome after cardiac arrest (CA), but standardized criteria for evaluation are lacking. To date, no prospective trial has systematically validated methods for diagnosing hypoxic-ischaemic encephalopathy (HIE) on CT after CA. We present a protocol for validation of pre-specified radiological criteria for assessment of HIE on CT for neuroprognostication after CA. Methods/design: This is a prospective observational international multicentre substudy of the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Patients still unconscious 48 hours post-arrest at 13 participating hospitals were routinely examined with CT. Original images will be evaluated by examiners blinded to clinical data using a standardized protocol. Qualitative assessment will include evaluation of absence/presence of "severe HIE". Radiodensities will be quantified in pre-specified regions of interest for calculation of grey-white matter ratios (GWR) at the basal ganglia level. Functional outcome will be dichotomized into good (modified Rankin Scale 0-3) and poor (modified Rankin Scale 4-6) at six months post-arrest. Prognostic accuracies for good and poor outcome will be presented as sensitivities and specificities with 95% confidence intervals (using pre-specified cut-offs for quantitative analysis), descriptive statistics (Area Under the Receiver Operating Characteristics Curve), inter- and intra-rater reliabilities according to STARD guidelines. Conclusions: The results from this prospective trial will validate a standardized approach to radiological evaluations of HIE on CT for prediction of functional outcome in comatose CA patients.The TTM2 trial and the TTM2 CT substudy are registered at ClinicalTrials.gov NCT02908308 and NCT03913065.

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators.

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Assessing left ventricular systolic function in shock: evaluation of echocardiographic parameters in intensive care.

INTRODUCTION: Assessing left ventricular (LV) systolic function in a rapid and reliable way can be challenging in the critically ill patient. The purpose of this study was to evaluate the feasibility and reliability of, as well as the association between, commonly used LV systolic parameters, by using serial transthoracic echocardiography (TTE). METHODS: Fifty patients with shock and mechanical ventilation were included. TTE examinations were performed daily for a total of 7 days. Methods used to assess LV systolic function were visually estimated, "eyeball" ejection fraction (EBEF), the Simpson single-plane method, mean atrioventricular plane displacement (AVPDm), septal tissue velocity imaging (TDIs), and velocity time integral in the left ventricular outflow tract (VTI). RESULTS: EBEF, AVPDm, TDIs, VTI, and the Simpson were obtained in 100%, 100%, 99%, 95% and 93%, respectively, of all possible examinations. The correlations between the Simpson and EBEF showed r values for all 7 days ranging from 0.79 to 0.95 (P < 0.01). the Simpson correlations with the other LV parameters showed substantial variation over time, with the poorest results seen for TDIs and AVPDm. The repeatability was best for VTI (interobserver coefficient of variation (CV) 4.8%, and intraobserver CV, 3.1%), and AVPDm (5.3% and 4.4%, respectively), and worst for the Simpson method (8.2% and 10.6%, respectively). CONCLUSIONS: EBEF and AVPDm provided the best, and Simpson, the worst feasibility when assessing LV systolic function in a population of mechanically ventilated, hemodynamically unstable patients. Additionally, the Simpson showed the poorest repeatability. We suggest that EBEF can be used instead of single-plane Simpson when assessing LV ejection fraction in this category of patients. TDIs and AVPDm, as markers of longitudinal function of the LV, are not interchangeable with LV ejection fraction.