BACKGROUND: Although bilirubin is a proven antioxidant substance and a protective factor against the development of various diseases, in emergency medicine, its increased concentration is considered solely a marker of organ damage and negative prognosis. However, clinical data on the role of bilirubin in cardiac arrest (CA) and reperfusion injury, are sparse. The presented study investigates the protective effects of increased serum bilirubin concentrations and genetic determinants (UGT1A1 promoter variations) on the outcomes of patients with refractory out-of-hospital CA (r-OHCA) in a randomized population. METHODS: Between March 1, 2013, and October 25, 2020, 256 randomized Prague OHCA patients with r-OHCA were evaluated for inclusion and categorized as having increased (>10 µmol/l) or low/normal serum bilirubin concentrations on hospital arrival and present or absent genetic variations for mild hyperbilirubinemia. The primary outcome was survival with a good neurological outcome (defined as cerebral performance category 1-2) 180 days after randomization. RESULTS: Finally, 164 patients were included in the bilirubin concentration analysis. Favorable neurological survival after 180 days occurred in 50 of 99 patients (50.5 %) in the group with higher initial serum bilirubin concentrations and 18 of 65 patients (27.7 %) in the low-bilirubin group (absolute difference 22.8 [8.1-37.5]; P = 0.006). The effect persisted also in multivariable analysis (OR for favorable outcome = 3.02 [95 % CI = 1.16-7.84]; P = 0.023). Genetic predisposition for mild hyperbilirubinemia was not associated with any patient outcomes. CONCLUSIONS: A higher initial serum bilirubin concentration predicts better outcomes in patients with refractory OHCA regardless of the treatment used. UGT1A1 gene promotor variations are not associated with refractory OHCA patient outcomes.

• Keywords
• Antioxidants, Bilirubin, Cardiac arrest, Genetic variations, Mechanical circulatory support, Oxidative stress,
• Publication type
• Journal Article MeSH

Higher cholesterol level is a risk factor of coronary artery disease, the major cause of sudden cardiac death (SCD). However, smaller studies observed worse outcomes in SCD patients having lower total and LDL-cholesterol levels. Therefore, the prognostic role of cholesterol itself in patients with SCD remains to be clarified. We aimed to assess the relationship of on-admission cholesterol level to the neurological outcome in a secondary analysis of the randomized Prague OHCA trial population (extracorporeal cardiopulmonary resuscitation (ECPR) vs. standard approach in refractory cardiac arrest). Of 256 included patients with refractory cardiac arrest, 123 were analyzed. The effects of total, HDL and non-HDL cholesterol levels drawn at admission on the best cerebral performance category (CPC) within 180 days were examined. Results are presented as median (interquartile range) and differences compared by the Wilcoxon test. Patients with CPC 1-2 had higher initial levels of total cholesterol [3.70 (3.23-4.27) mmol/L vs. 2.98 (2.35-4.02) mmol/L, p = 0.005], non-HDL cholesterol [2.68 (2.08-3.24) vs. 1.93 (1.62-2.97) mmol/L, p = 0.007 and HDL-cholesterol [0.93 (0.67-1.07) mmol/L vs. 0.74 (0.49-0.96) mmol/L, p = 0.014] compared to patients with CPC 3-5. Chronic use of statins did not influence the outcome. Only the low levels of total and non-HDL cholesterol remained consistent predictors of poor neurological outcomes in all patients and in both separate arms. Lower total and non-HDL cholesterol levels on admission are associated with worse neurological outcomes in patients with refractory cardiac arrest treated by both ECPR and standard approach.

• Keywords
• Cholesterol, Extracorporeal membrane oxygenation, Refractory cardiac arrest, Resuscitation,
• MeSH
• Cholesterol * blood   MeSH
• Cholesterol, HDL blood   MeSH
• Cardiopulmonary Resuscitation MeSH
• Cholesterol, LDL blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Patient Admission MeSH
• Prognosis MeSH
• Risk Factors MeSH
• Aged MeSH
• Heart Arrest * blood   therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Cholesterol * MeSH
• Cholesterol, HDL MeSH
• Cholesterol, LDL MeSH

BACKGROUND: The outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined using frequentist methods, resulting in a dichotomous interpretation of results based on p-values rather than in the probability of clinically relevant treatment effects. To determine such a probability of a clinically relevant ECPR-based treatment effect on neurological outcomes, the authors of these trials performed a Bayesian meta-analysis of the totality of randomized ECPR evidence. METHODS: A systematic search was applied to three electronic databases. Randomized trials that compared ECPR-based treatment with conventional CPR for refractory out-of-hospital cardiac arrest were included. The study was preregistered in INPLASY (INPLASY2023120060). The primary Bayesian hierarchical meta-analysis estimated the difference in 6-month neurologically favorable survival in patients with all rhythms, and a secondary analysis assessed this difference in patients with shockable rhythms (Bayesian hierarchical random-effects model). Primary Bayesian analyses were performed under vague priors. Outcomes were formulated as estimated median relative risks, mean absolute risk differences, and numbers needed to treat with corresponding 95% credible intervals (CrIs). The posterior probabilities of various clinically relevant absolute risk difference thresholds were estimated. RESULTS: Three randomized trials were included in the analysis (ECPR, n = 209 patients; conventional CPR, n = 211 patients). The estimated median relative risk of ECPR for 6-month neurologically favorable survival was 1.47 (95%CrI 0.73-3.32) with a mean absolute risk difference of 8.7% (- 5.0; 42.7%) in patients with all rhythms, and the median relative risk was 1.54 (95%CrI 0.79-3.71) with a mean absolute risk difference of 10.8% (95%CrI - 4.2; 73.9%) in patients with shockable rhythms. The posterior probabilities of an absolute risk difference > 0% and > 5% were 91.0% and 71.1% in patients with all rhythms and 92.4% and 75.8% in patients with shockable rhythms, respectively. CONCLUSION: The current Bayesian meta-analysis found a 71.1% and 75.8% posterior probability of a clinically relevant ECPR-based treatment effect on 6-month neurologically favorable survival in patients with all rhythms and shockable rhythms. These results must be interpreted within the context of the reported credible intervals and varying designs of the randomized trials. REGISTRATION: INPLASY (INPLASY2023120060, December 14th, 2023, https://doi.org/10.37766/inplasy2023.12.0060 ).

• Keywords
• Bayesian statistical inference, Conventional cardiopulmonary resuscitation, Extracorporeal cardiopulmonary resuscitation, Neurologically favorable survival, Out-of-hospital cardiac arrest, Randomized controlled trials,
• MeSH
• Bayes Theorem * MeSH
• Cardiopulmonary Resuscitation * methods   standards   MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation methods   MeSH
• Randomized Controlled Trials as Topic methods   MeSH
• Treatment Outcome MeSH
• Out-of-Hospital Cardiac Arrest * therapy   mortality   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

BACKGROUND: Randomized data evaluating the impact of the extracorporeal cardiopulmonary resuscitation (ECPR) approach on long-term clinical outcomes in patients with refractory out-of-hospital cardiac arrest (OHCA) are lacking. The objective of this follow-up study was to assess the long-term clinical outcomes of the ECPR-based versus CCPR approach. METHODS: The Prague OHCA trial was a single-center, randomized, open-label trial. Patients with witnessed refractory OHCA of presumed cardiac origin, without return of spontaneous circulation, were randomized during ongoing resuscitation on scene to conventional CPR (CCPR) or an ECPR-based approach (intra-arrest transport, ECPR if ROSC is not achieved prehospital and immediate invasive assessment). RESULTS: From March 2013 to October 2020, 264 patients were randomized during ongoing resuscitation on scene, and 256 patients were enrolled. Long-term follow-up was performed 5.3 (interquartile range 3.8-7.2) years after initial randomization and was completed in 255 of 256 patients (99.6%). In total, 34/123 (27.6%) patients in the ECPR-based group and 26/132 (19.7%) in the CCPR group were alive (log-rank P = 0.01). There were no significant differences between the treatment groups in the neurological outcome, survival after hospital discharge, risk of hospitalization, major cardiovascular events and quality of life. Of long-term survivors, 1/34 (2.9%) in the ECPR-based arm and 1/26 (3.8%) in the CCPR arm had poor neurological outcome (both patients had a cerebral performance category score of 3). CONCLUSIONS: Among patients with refractory OHCA, the ECPR-based approach significantly improved long-term survival. There were no differences in the neurological outcome, major cardiovascular events and quality of life between the groups, but the trial was possibly underpowered to detect a clinically relevant difference in these outcomes. Trial registration ClinicalTrials.gov Identifier: NCT01511666, Registered 19 January 2012.

• Keywords
• Extracorporeal cardiopulmonary resuscitation, Extracorporeal membrane oxygenation, Long-term, Out-of-hospital cardiac arrest, Quality of life,
• MeSH
• Time Factors MeSH
• Cardiopulmonary Resuscitation * MeSH
• Quality of Life MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Retrospective Studies MeSH
• Out-of-Hospital Cardiac Arrest * therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Neurological damage remains the leading cause of death in cardiac arrest victims with early neuroprognostication being the cornerstone of the decision-making process to continue or discontinue advanced treatments. In this study, we aimed to find markers of favorable and unfavorable outcome on early brain computed tomography (CT) in patients after prolonged out-of-hospital cardiac arrest (OHCA) treated both by conventional and extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: In a secondary analysis of the Prague OHCA study, patients who underwent brain CT within 36 hours after cardiac arrest were identified. Qualitative findings (brain edema, hemorrhage) and quantitative measurements [attenuation of grey matter structures and grey-to-white matter attenuation ratio (GWR)] between patients with cerebral performance category (CPC) of 1-2 (favorable outcome) and 3-5 (unfavorable outcome) within 180 days after the event were compared. RESULTS: In 45 eligible patients, intracranial edema (n=16, 50%) was present in patients with CPC 3-5 only (n=32, 71%). Attenuation of brain structures and GWR did not differ between patients with favorable and unfavorable outcomes. However, the GWR in the caudate and putamen of most CPC 1-2 patients was within a narrow range of values (1.18 to 1.30 and 1.20 to 1.33) that separated patients with CPC 1-2 from CPC 3-5 with a sensitivity of 78% and 66% a specificity of 85% and 100%, and area under the curve （AUC） of 0.86 (P=0.0001) and 0.77 (P=0.0053), respectively. Patients treated by ECPR had lower attenuation in the centrum semiovale (28.3±2.7) compared to those who were not (31.0±2.8, P=0.003). The most common causes of death in CPC 3-5 patients were brain death in 13 (41%) patients, multiorgan failure in 12 (38%), and cardiac rearrest in 4 (13%). CONCLUSIONS: Both decreased and increased grey-to-white matter differentiation in the putamen and caudate on early non-contrast brain CT after prolonged OHCA indicate poor neurological outcome within 180 days after cardiac arrest.

• Keywords
• Cardiac arrest, brain edema, computed tomography (CT), prognosis,
• Publication type
• Journal Article MeSH

Extracorporeal cardiopulmonary resuscitation is a promising treatment for refractory out-of-hospital cardiac arrest. Three recent randomized trials (ARREST trial, Prague OHCA study, and INCEPTION trial) that addressed the clinical benefit of extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest yielded seemingly diverging results. The evidence for extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest, derived from three recent randomized controlled trials, is not contradictory but rather complementary. Excellent results can be achieved with a very high level of dedication, provided that strict selection criteria are applied. However, pragmatic implementation of extracorporeal cardiopulmonary resuscitation does not necessarily lead to improved outcome of refractory out-of-hospital cardiac arrest. Centres that are performing extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest or aspire to do so should critically evaluate whether they are able to meet the pre-requisites that are needed to conduct an effective extracorporeal cardiopulmonary resuscitation programme.

• Keywords
• Efficacy and effectiveness, Extracorporeal cardiopulmonary resuscitation, Randomized controlled trials, Review,
• MeSH
• Cardiopulmonary Resuscitation * MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic MeSH
• Out-of-Hospital Cardiac Arrest * therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Refractory out-of-hospital cardiac arrest (OHCA) treated with standard advanced cardiac life support (ACLS) has poor outcomes. Transport to hospital followed by in-hospital extracorporeal cardiopulmonary resuscitation (ECPR) initiation may improve outcomes. We performed a pooled individual patient data analysis of two randomised controlled trials evaluating ECPR based approach in OHCA. METHODS: The individual patient data from two published randomised controlled trials (RCTs) were pooled: ARREST (enrolled Aug 2019-June 2020; NCT03880565) and PRAGUE-OHCA (enrolled March 1, 2013-Oct 25, 2020; NCT01511666). Both trials enrolled patients with refractory OHCA and compared: intra-arrest transport with in-hospital ECPR initiation (invasive approach) versus continued standard ACLS. The primary outcome was 180-day survival with favourable neurological outcome (defined as Cerebral Performance Category 1-2). Secondary outcomes included: cumulative survival at 180 days, 30-day favourable neurological survival, and 30-day cardiac recovery. Risk of bias in each trial was assessed by two independent reviewers using the Cochrane risk-of-bias tool. Heterogeneity was assessed via Forest plots. FINDINGS: The two RCTs included 286 patients. Of those randomised to the invasive (n = 147) and standard (n = 139) groups, respectively: the median age was 57 (IQR 47-65) and 58 years (IQR 48-66), and the median duration of resuscitation was 58 (IQR 43-69) and 49 (IQR 33-71) minutes (p = 0.17). In a modified intention to treat analysis, 45 (32.4%) in the invasive and 29 (19.7%) patients in the standard arm survived to 180 days with a favourable neurological outcome [absolute difference (AD), 95% CI: 12.7%, 2.6-22.7%, p = 0.015]. Forty-seven (33.8%) and 33 (22.4%) patients survived to 180 days [HR 0.59 (0.43-0.81); log rank test p = 0.0009]. At 30 days, 44 (31.7%) and 24 (16.3%) patients had favourable neurological outcome (AD 15.4%, 5.6-25.1%, p = 0.003), 60 (43.2%), and 46 (31.3%) patients had cardiac recovery (AD: 11.9%, 0.7-23%, p = 0.05), in the invasive and standard arms, respectively. The effect was larger in patients presenting with shockable rhythms (AD 18.8%, 7.6-29.4; p = 0.01; HR 2.26 [1.23-4.15]; p = 0.009) and prolonged CPR (>45 min; HR 3.99 (1.54-10.35); p = 0.005). INTERPRETATION: In patients with refractory OHCA, the invasive approach significantly improved 30- and 180-day neurologically favourable survival. FUNDING: None.

• Keywords
• Cardiac arrest, Extracorporeal circulation, Invasive, Resuscitation,
• Publication type
• Journal Article MeSH

BACKGROUND: Survival rates in refractory out-of-hospital cardiac arrest (OHCA) remain low with conventional advanced cardiac life support (ACLS). Extracorporeal life support (ECLS) implantation during ongoing resuscitation, a method called extracorporeal cardiopulmonary resuscitation (ECPR), may increase survival. This study examined whether ECPR is associated with improved outcomes. METHODS: Prague OHCA trial enrolled adults with a witnessed refractory OHCA of presumed cardiac origin. In this secondary analysis, the effect of ECPR on 180-day survival using Kaplan-Meier estimates and Cox proportional hazard model was examined. RESULTS: Among 256 patients (median age 58 years, 83% male) with median duration of resuscitation 52.5 min (36.5-68), 83 (32%) patients achieved prehospital ROSC during ongoing conventional ACLS prehospitally, 81 (32%) patients did not achieve prehospital ROSC with prolonged conventional ACLS, and 92 (36%) patients did not achieve prehospital ROSC and received ECPR. The overall 180-day survival was 51/83 (61.5%) in patients with prehospital ROSC, 1/81 (1.2%) in patients without prehospital ROSC treated with conventional ACLS and 22/92 (23.9%) in patients without prehospital ROSC treated with ECPR (log-rank p < 0.001). After adjustment for covariates (age, sex, initial rhythm, prehospital ROSC status, time of emergency medical service arrival, resuscitation time, place of cardiac arrest, percutaneous coronary intervention status), ECPR was associated with a lower risk of 180-day death (HR 0.21, 95% CI 0.14-0.31; P < 0.001). CONCLUSIONS: In this secondary analysis of the randomized refractory OHCA trial, ECPR was associated with improved 180-day survival in patients without prehospital ROSC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01511666, Registered 19 January 2012.

• Keywords
• Extracorporeal cardiopulmonary resuscitation, Extracorporeal life support, Extracorporeal membrane oxygenation, Out-of-hospital cardiac arrest, Return of spontaneous circulation,
• MeSH
• Adult MeSH
• Cardiopulmonary Resuscitation * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation * methods   MeSH
• Advanced Cardiac Life Support MeSH
• Emergency Medical Services * methods   MeSH
• Out-of-Hospital Cardiac Arrest * therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

IMPORTANCE: Out-of-hospital cardiac arrest (OHCA) has poor outcome. Whether intra-arrest transport, extracorporeal cardiopulmonary resuscitation (ECPR), and immediate invasive assessment and treatment (invasive strategy) is beneficial in this setting remains uncertain. OBJECTIVE: To determine whether an early invasive approach in adults with refractory OHCA improves neurologically favorable survival. DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized clinical trial in Prague, Czech Republic, of adults with a witnessed OHCA of presumed cardiac origin without return of spontaneous circulation. A total of 256 participants, of a planned sample size of 285, were enrolled between March 2013 and October 2020. Patients were observed until death or day 180 (last patient follow-up ended on March 30, 2021). INTERVENTIONS: In the invasive strategy group (n = 124), mechanical compression was initiated, followed by intra-arrest transport to a cardiac center for ECPR and immediate invasive assessment and treatment. Regular advanced cardiac life support was continued on-site in the standard strategy group (n = 132). MAIN OUTCOMES AND MEASURES: The primary outcome was survival with a good neurologic outcome (defined as Cerebral Performance Category [CPC] 1-2) at 180 days after randomization. Secondary outcomes included neurologic recovery at 30 days (defined as CPC 1-2 at any time within the first 30 days) and cardiac recovery at 30 days (defined as no need for pharmacological or mechanical cardiac support for at least 24 hours). RESULTS: The trial was stopped at the recommendation of the data and safety monitoring board when prespecified criteria for futility were met. Among 256 patients (median age, 58 years; 44 [17%] women), 256 (100%) completed the trial. In the main analysis, 39 patients (31.5%) in the invasive strategy group and 29 (22.0%) in the standard strategy group survived to 180 days with good neurologic outcome (odds ratio [OR], 1.63 [95% CI, 0.93 to 2.85]; difference, 9.5% [95% CI, -1.3% to 20.1%]; P = .09). At 30 days, neurologic recovery had occurred in 38 patients (30.6%) in the invasive strategy group and in 24 (18.2%) in the standard strategy group (OR, 1.99 [95% CI, 1.11 to 3.57]; difference, 12.4% [95% CI, 1.9% to 22.7%]; P = .02), and cardiac recovery had occurred in 54 (43.5%) and 45 (34.1%) patients, respectively (OR, 1.49 [95% CI, 0.91 to 2.47]; difference, 9.4% [95% CI, -2.5% to 21%]; P = .12). Bleeding occurred more frequently in the invasive strategy vs standard strategy group (31% vs 15%, respectively). CONCLUSIONS AND RELEVANCE: Among patients with refractory out-of-hospital cardiac arrest, the bundle of early intra-arrest transport, ECPR, and invasive assessment and treatment did not significantly improve survival with neurologically favorable outcome at 180 days compared with standard resuscitation. However, the trial was possibly underpowered to detect a clinically relevant difference. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01511666.

• MeSH
• Time-to-Treatment MeSH
• Cardiopulmonary Resuscitation methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation MeSH
• Aged MeSH
• Transportation of Patients * MeSH
• Out-of-Hospital Cardiac Arrest diagnosis   mortality   therapy   MeSH
• Medical Futility MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

INTRODUCTION: Veno-arterial extracorporeal life support (ECLS) is increasingly being used to treat rapidly progressing or severe cardiogenic shock. However, it has been repeatedly shown that increased afterload associated with ECLS significantly diminishes left ventricular (LV) performance. The objective of the present study was to compare LV function and coronary flow during standard continuous-flow ECLS support and electrocardiogram (ECG)-synchronized pulsatile ECLS flow in a porcine model of cardiogenic shock. METHODS: Sixteen female swine (mean body weight 45 kg) underwent ECLS implantation under general anesthesia and artificial ventilation. Subsequently, acute cardiogenic shock, with documented signs of tissue hypoperfusion, was induced by initiating global myocardial hypoxia. Hemodynamic cardiac performance variables and coronary flow were then measured at different rates of continuous or pulsatile ECLS flow (ranging from 1 L/min to 4 L/min) using arterial and venous catheters, a pulmonary artery catheter, an LV pressure-volume loop catheter, and a Doppler coronary guide-wire. RESULTS: Myocardial hypoxia resulted in declines in mean cardiac output to 1.7±0.7 L/min, systolic blood pressure to 64±22 mmHg, and LV ejection fraction (LVEF) to 22±7%. Synchronized pulsatile flow was associated with a significant reduction in LV end-systolic volume by 6.2 mL (6.7%), an increase in LV stroke volume by 5.0 mL (17.4%), higher LVEF by 4.5% (18.8% relative), cardiac output by 0.37 L/min (17.1%), and mean arterial pressure by 3.0 mmHg (5.5%) when compared with continuous ECLS flow at all ECLS flow rates (P<0.05). At selected ECLS flow rates, pulsatile flow also reduced LV end-diastolic pressure, end-diastolic volume, and systolic pressure. ECG-synchronized pulsatile flow was also associated with significantly increased (7% to 22%) coronary flow at all ECLS flow rates. CONCLUSION: ECG-synchronized pulsatile ECLS flow preserved LV function and coronary flow compared with standard continuous-flow ECLS in a porcine model of cardiogenic shock.

• MeSH
• Electrocardiography methods   MeSH
• Ventricular Function, Left physiology   MeSH
• Hemodynamics MeSH
• Shock, Cardiogenic pathology   physiopathology   therapy   MeSH
• Coronary Vessels physiopathology   MeSH
• Coronary Circulation physiology   MeSH
• Extracorporeal Membrane Oxygenation methods   MeSH
• Disease Models, Animal * MeSH
• Swine * MeSH
• Pulsatile Flow physiology   MeSH
• Life Support Care methods   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH