Efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II trial): study protocol for a randomized controlled trial.
ABSTRACT: Hydrogen gas inhalation (HI) improved survival and neurological outcomes in an animal model of post-cardiac arrest syndrome (PCAS). The feasibility and safety of HI for patients with PCAS was confirmed in a pilot study. The objective of this study is to evaluate the efficacy of HI for patients with PCAS.The efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II) trial is an investigator-initiated, randomized, double-blind, placebo-controlled trial designed to enroll 360 adult comatose (Glasgow Coma Scale score?
Project description:The aim of this study was to develop a scoring system for identifying the post-cardiac arrest syndrome (PCAS) patients with a good potential for recovery prior to the initiation of induced therapeutic hypothermia.A multi-center, retrospective, observational study was performed. Data of a total of 151 consecutive adults who underwent induced hypothermia after cardiac arrest (77 learning cases from two hospitals and 74 validation cases from two other hospitals) were analyzed.In the learning set, 8 factors (initial rhythm, witnessed status and time until return of spontaneous circulation, pH, serum lactate, motor score according to the Glasgow Coma Scale (GCS), gray matter attenuation to white matter attenuation ratio (GWR), serum albumin, and hemoglobin) were found to be strongly correlated with the neurological outcomes. A tentative scoring system was created from the learning data using these factors, and the predictive accuracy (sensitivity and specificity) was evaluated in terms of both internal validation (0.85 and 0.84) and external validation (cutoff 50%: 0.95 and 0.90, 30%: 0.87 and 0.98, 15%: 0.67 and 1.00). Finally, using all the data, we established a post-Cardiac Arrest Syndrome for induced Therapeutic hypothermia (CAST) score to predict the neurologic prognosis prior to initiation of induced hypothermia.The CAST score was developed to predict the neurological outcomes of PCAS patients treated by induced hypothermia. The likelihood of good recovery at 30 days was extremely low in PCAS patients with a CAST score of ?15%. Prospective validation of the score is needed in the future.
Project description:BACKGROUND:The TTH48 trial aims to determine whether prolonged duration (48 hours) of targeted temperature management (TTM) at 33 (±1) °C results in better neurological outcomes compared to standard duration (24 hours) after six months in comatose out-of-hospital cardiac arrest (OHCA) patients. METHODS:TTH48 is an investigator-initiated, multicentre, assessor-blinded, randomised, controlled superiority trial of 24 and 48 hours of TTM at 33 (±1) ° C performed in 355 comatose OHCA patients aged 18 to 80 years who were admitted to ten intensive care units (ICUs) in six Northern European countries. The primary outcome of the study is the Cerebral Performance Category (CPC) score observed at six months after cardiac arrest. CPC scores of 1 and 2 are defined as good neurological outcomes, and CPC scores of 3, 4 and 5 are defined as poor neurological outcomes. The secondary outcomes are as follows: mortality within six months after cardiac arrest, CPC at hospital discharge, Glasgow Coma Scale (GCS) score on day 4, length of stay in ICU and at hospital and the presence of any adverse events such as cerebral, circulatory, respiratory, gastrointestinal, renal, metabolic measures, infection or bleeding. With the planned sample size, we have 80% power to detect a 15% improvement in good neurological outcomes at a two-sided statistical significance level of 5%. DISCUSSION:We present a detailed statistical analysis protocol (SAP) that specifies how primary and secondary outcomes should be evaluated. We also predetermine covariates for adjusted analyses and pre-specify sub-groups for sensitivity analyses. This pre-planned SAP will reduce analysis bias and add validity to the findings of this trial on the effect of length of TTM on important clinical outcomes after cardiac arrest. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01689077 , 17 September 2012.
Project description:Predicting neurological outcomes in patients with post-cardiac arrest syndrome (PCAS) is crucial for identifying those who will benefit from intensive care. We evaluated the predictive value of 18F-FDG PET. PCAS was induced in Sprague Dawley rats. Baseline and post-3-hour images were acquired. Standardized uptake value (SUV) changes before and after PCAS induction (SUV<sub>delta</sub>) and SUV ratios (SUVR) of regional SUV normalized to the whole brain SUV were obtained. The Morris water maze (MWM) test was performed after 2 weeks to evaluate neurological outcomes and rats were classified into two groups based on the result. Of 18 PCAS rats, 8 were classified into the good outcome group. The SUV<sub>delta</sub> of forebrain regions were significantly decreased in good outcome group (p?<?0.05), while the SUV<sub>delta</sub> of hindbrain regions were not significantly different according to outcomes. The SUVR of forebrain regions were significantly higher and the SUVR of hindbrain regions were significantly lower in good outcome group (p?<?0.05). Forebrain-to-hindbrain ratio predicted a good neurological outcome with a sensitivity of 90% and specificity of 100% using an optimal cutoff value of 1.22 (AUC 0.969, p?<?0.05). These results suggest the potential utility of 18F-FDG PET in the early prediction of neurological outcomes in PCAS.
Project description:Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung-brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.
Project description:BACKGROUND:Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose at admission are at high risk of morbidity and mortality. This has been attributed to the post-cardiac arrest syndrome (PCAS) which encompasses multiple interacting components, including systemic inflammation. Elevated levels of circulating interleukin-6 (IL-6), a pro-inflammatory cytokine, is associated with worse outcomes in OHCA patients, including higher vasopressor requirements and higher mortality rates. In this study, we aim to reduce systemic inflammation after OHCA by administering a single infusion of tocilizumab, an IL-6 receptor antibody approved for use for other indications. METHODS:Investigator-initiated, double-blinded, placebo-controlled, single-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Brief inclusion criteria: OHCA of presumed cardiac cause, persistent unconsciousness, age???18?years. INTERVENTION:80 patients will be randomized in a 1:1 ratio to a single 1-h intravenous infusion of either tocilizumab or placebo (NaCl). During the study period, patients will receive standard of care, including sedation and targeted temperature management of 36 ° for at least 24?h, vasopressors and/or inotropes as/if needed, prophylactic antibiotics, and any additional treatment at the discretion of the treating physician. Blood samples are drawn for measurements of biomarkers included in the primary and secondary endpoints during the initial 72?h. Primary endpoint: reduction in C-reactive protein (CRP). Secondary endpoints (abbreviated): cytokine levels, markers of brain, cardiac, kidney and liver damage, hemodynamic and hemostatic function, adverse events, and follow-up assessment of cerebral function and mortality. DISCUSSION:We hypothesize that reducing the effect of circulating IL-6 by administering an IL-6 receptor antibody will mitigate the systemic inflammatory response and thereby modify the severity of PCAS, in turn leading to lessened vasopressor use, more normal hemodynamics, and better organ function. This will be assessed by primarily focusing on hemodynamics and biomarkers of organ damage during the initial 72?h. In addition, pro-inflammatory and anti-inflammatory cytokines will be measured to assess if cytokine patterns are modulated by IL-6 receptor blockage. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03863015 ; submitted February 22, 2019, first posted March 5, 2019. EudraCT: 2018-002686-19; date study was authorized to proceed: November 7, 2018.
Project description:Oxidative stress plays a key role in the pathophysiology of post-cardiac arrest syndrome. Molecular hydrogen reduces oxidative stress and exerts anti-inflammatory effects in an animal model of cardiac arrest. However, its effect on human post-cardiac arrest syndrome is unclear. We consecutively enrolled five comatose post-cardiac arrest patients (three males; mean age, 65 ± 15 years; four cardiogenic, one septic cardiac arrest) and evaluated temporal changes in oxidative stress markers and cytokines with inhaled hydrogen. All patients were treated with target temperature management. Hydrogen gas inhalation (2% hydrogen with titrated oxygen) was initiated upon admission for 18 h. Blood hydrogen concentrations, plasma and urine oxidative stress markers (derivatives of reactive oxygen metabolites, biological antioxidant potential, 8-hydroxy-2'-deoxyguanosine, N?-hexanoyl-lysine, lipid hydroperoxide), and cytokines (interleukin-6 and tumor necrosis factor-?) were measured before and 3, 9, 18, and 24 h after hydrogen gas inhalation. Arterial hydrogen concentration was measurable and it was equilibrated with inhaled hydrogen. Oxidative stress was reduced and cytokine levels were unchanged in cardiogenic patients, whereas oxidative stress was unchanged and cytokine levels were diminished in the septic patient. The effect of inhaled hydrogen on oxidative stress and cytokines in comatose post-cardiac arrest patients remains indefinite because of methodological weaknesses.
Project description:Electroencephalography (EEG) is widely used to assess neurological prognosis in patients who are comatose after cardiac arrest, but its value is limited by varying definitions of pathological patterns and by inter-rater variability. The American Clinical Neurophysiology Society (ACNS) has recently proposed a standardized EEG-terminology for critical care to address these limitations.In the TTM-trial, 399 post cardiac arrest patients who remained comatose after rewarming underwent a routine EEG. The presence of clinical seizures, use of sedatives and antiepileptic drugs during the EEG-registration were prospectively documented.A well-defined terminology for interpreting post cardiac arrest EEGs is critical for the use of EEG as a prognostic tool.The TTM-trial is registered at ClinicalTrials.gov (NCT01020916).
Project description:Background Targeted temperature management ( TTM ) is a recommended treatment modality to improve neurological outcomes in patients with out-of-hospital cardiac arrest. The impact of the duration from hospital admission to TTM initiation (door-to- TTM ; DTT ) on clinical outcomes has not been well elucidated. We hypothesized that shorter DTT initiation intervals would be associated with improved survival with favorable neurological outcome. Methods and Results We performed a post hoc analysis of nontraumatic paramedic-treated out-of-hospital cardiac arrests. The primary outcome was favorable neurological status at hospital discharge, with a secondary outcome of survival to discharge. We fit a logistic regression analysis to determine the association of early compared with delayed DTT , dichotomized by the median DTT duration, and outcomes. Of 3805 patients enrolled in the CCC (Continuous Chest Compressions) Trial in British Columbia, 570 were included in this analysis. There was substantial variation in DTT among patients receiving TTM . The median DTT duration was 122 minutes (interquartile range 35-218). Favorable neurological outcomes in the early and delayed DTT groups were 48% and 38%, respectively. Compared with delayed DTT (interquartile range 167-319 minutes), early DTT (interquartile range 20-81 minutes) was associated with survival (adjusted odds ratio 1.56, 95% CI 1.02-2.38) but not with favorable neurological outcomes (adjusted odds ratio 1.45, 95% CI , 0.94-2.22) at hospital discharge. Conclusions There was wide variability in the initiation of TTM among comatose out-of-hospital cardiac arrest survivors. Initiation of TTM within 122 minutes of hospital admission was associated with improved survival. These results support in-hospital efforts to achieve early DTT among out-of-hospital cardiac arrest patients admitted to the hospital.
Project description:Early prognosis in comatose survivors after cardiac arrest due to ventricular fibrillation (VF) is unreliable, especially in patients undergoing mild hypothermia. We aimed at developing a reliable risk-score to enable early prediction of cerebral performance and survival.Sixty-one out of 239 consecutive patients undergoing mild hypothermia after cardiac arrest, with eventual return of spontaneous circulation (ROSC), and comatose status on admission fulfilled the inclusion criteria. Background clinical variables, VF time and frequency domain fundamental variables were considered. The primary and secondary outcomes were a favorable neurological performance (FNP) during hospitalization and survival to hospital discharge, respectively. The predictive model was developed in a retrospective cohort (n = 32; September 2006-September 2011, 48.5 ± 10.5 months of follow-up) and further validated in a prospective cohort (n = 29; October 2011-July 2013, 5 ± 1.8 months of follow-up).FNP was present in 16 (50.0%) and 21 patients (72.4%) in the retrospective and prospective cohorts, respectively. Seventeen (53.1%) and 21 patients (72.4%), respectively, survived to hospital discharge. Both outcomes were significantly associated (p < 0.001). Retrospective multivariate analysis provided a prediction model (sensitivity = 0.94, specificity = 1) that included spectral dominant frequency, derived power density and peak ratios between high and low frequency bands, and the number of shocks delivered before ROSC. Validation on the prospective cohort showed sensitivity = 0.88 and specificity = 0.91. A model-derived risk-score properly predicted 93% of FNP. Testing the model on follow-up showed a c-statistic ? 0.89.A spectral analysis-based model reliably correlates time-dependent VF spectral changes with acute cerebral injury in comatose survivors undergoing mild hypothermia after cardiac arrest.
Project description:BACKGROUND: The prediction of neurological outcome in comatose patients after cardiac arrest has major ethical and socioeconomic implications. The purpose of this study was to assess the capability of serum neuron-specific enolase (NSE), a biomarker of hypoxic brain damage, to predict death or vegetative state in comatose cardiac-arrest survivors. METHODS: We conducted a prospective observational cohort study in one university hospital and one general hospital Intensive Care Unit (ICU). All consecutive patients who suffered cardiac arrest and were subsequently admitted from June 2007 to February 2009 were considered for inclusion in the study. Patients who died or awoke within the first 48 hours of admission were excluded from the analysis. Patients were followed for 3 months or until death after cardiopulmonary resuscitation. The Cerebral Performance Categories scale (CPC) was used as the outcome measure; a CPC of 4-5 was regarded as a poor outcome, and a CPC of 1-3 a good outcome. Measurement of serum NSE was performed at 24 h and at 72 h after the time of cardiac arrest using an enzyme immunoassay. Clinicians were blinded to NSE results. RESULTS: Ninety-seven patients were included. All patients were actively supported during the first days following cardiac arrest. Sixty-five patients (67%) underwent cooling after resuscitation. At 3 months 72 (74%) patients had a poor outcome (CPC 4-5) and 25 (26%) a good outcome (CPC 1-3). The median and Interquartile Range [IQR] levels of NSE at 24 h and at 72 h were significantly higher in patients with poor outcomes: NSE at 24 h: 59.4 ng/mL [37-106] versus 28.8 ng/mL [18-41] (p < 0.0001); and NSE at 72 h: 129.5 ng/mL [40-247] versus 15.7 ng/mL [12-19] (p < 0.0001). The Receiver Operator Characteristics (ROC) curve for poor outcome for the highest observed NSE value for each patient determined a cut-off value for NSE of 97 ng/mL to predict a poor neurological outcome with a specificity of 100% [95% CI = 87-100] and a sensitivity of 49% [95% CI = 37-60]. However, an approach based on a combination of SSEPs, NSE and clinical-EEG tests allowed to increase the number of patients (63/72 (88%)) identified as having a poor outcome and for whom intensive treatment could be regarded as futile. CONCLUSION: NSE levels measured early in the course of patient care for those who remained comatose after cardiac arrest were significantly higher in patients with outcomes of death or vegetative state. In addition, we provide a cut-off value for NSE (> 97 ng/mL) with 100% positive predictive value of poor outcome. Nevertheless, for decisions concerning the continuation of treatment in this setting, we emphasize that an approach based on a combination of SSEPs, NSE and clinical EEG would be more accurate for identifying patients with a poor neurological outcome.