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Characterization of mitochondrial injury after cardiac arrest (COMICA).

ABSTRACT: Mitochondrial injury post-cardiac arrest has been described in pre-clinical settings but the extent to which this injury occurs in humans remains largely unknown. We hypothesized that increased levels of mitochondrial biomarkers would be associated with mortality and neurological morbidity in post-cardiac arrest subjects.We performed a prospective multicenter study of post-cardiac arrest subjects. Inclusion criteria were comatose adults who suffered an out-of-hospital cardiac arrest. Mitochondrial biomarkers were measured at 0, 12, 24, 36 and 48h after return of spontaneous circulation as well as in healthy controls.Out of 111 subjects enrolled, 102 had evaluable samples at 0h. Cardiac arrest subjects had higher baseline cytochrome c levels compared to controls (2.18ng/mL [0.74, 7.74] vs. 0.16ng/mL [0.03, 0.91], p<0.001), and subjects who died had higher 0h cytochrome c levels compared to survivors (3.66ng/mL [1.40, 14.9] vs. 1.27ng/mL [0.16, 2.37], p<0.001). There were significantly higher Ribonuclease P (RNaseP) (3.3 [1.2, 5.7] vs. 1.2 [0.8, 1.2], p<0.001) and Beta-2microglobulin (B2M) (12.0 [1.0, 22.9], vs. 0.6 [0.6, 1.3], p<0.001) levels in cardiac arrest subjects at baseline compared to the control subjects. There were no differences between survivors and non-survivors for mitochondrial DNA, nuclear DNA, or cell free DNA.Cytochrome c was increased in post- cardiac arrest subjects compared to controls, and in post-cardiac arrest non-survivors compared to survivors. Nuclear DNA and cell free DNA was increased in plasma of post-cardiac arrest subjects. There were no differences in mitochondrial DNA, nuclear DNA, or cell free DNA between survivors and non-survivors. Mitochondrial injury markers showed mixed results in the post-cardiac arrest period. Future research needs to investigate these differences.

SUBMITTER: Donnino MW

PROVIDER: S-EPMC5497747 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Characterization of mitochondrial injury after cardiac arrest (COMICA).

Donnino Michael W MW Liu Xiaowen X Andersen Lars W LW Rittenberger Jon C JC Abella Benjamin S BS Gaieski David F DF Ornato Joseph P JP Gazmuri Raúl J RJ Grossestreuer Anne V AV Cocchi Michael N MN Abbate Antonio A Uber Amy A Clore John J Peberdy Mary Anne MA Callaway Clifton W CW

Resuscitation 20170123

<h4>Introduction</h4>Mitochondrial injury post-cardiac arrest has been described in pre-clinical settings but the extent to which this injury occurs in humans remains largely unknown. We hypothesized that increased levels of mitochondrial biomarkers would be associated with mortality and neurological morbidity in post-cardiac arrest subjects.<h4>Methods</h4>We performed a prospective multicenter study of post-cardiac arrest subjects. Inclusion criteria were comatose adults who suffered an out-of ...[more]

PMID: 28126408

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Project description:OBJECTIVES:Cardiac arrest etiology may be an important source of between-patient heterogeneity, but the impact of etiology on organ injury is unknown. We tested the hypothesis that asphyxial cardiac arrest results in greater neurologic injury than cardiac etiology cardiac arrest (ventricular fibrillation cardiac arrest), whereas ventricular fibrillation cardiac arrest results in greater cardiovascular dysfunction after return of spontaneous circulation. DESIGN:Prospective observational human and randomized animal study. SETTING:University laboratory and ICUs. PATIENTS:Five-hundred forty-three cardiac arrest patients admitted to ICU. SUBJECTS:Seventy-five male Sprague-Dawley rats. INTERVENTIONS:We examined neurologic and cardiovascular injury in Isoflurane-anesthetized rat cardiac arrest models matched by ischemic time. Hemodynamic and neurologic outcomes were assessed after 5 minutes no flow asphyxial cardiac arrest or ventricular fibrillation cardiac arrest. Comparison was made to injury patterns observed after human asphyxial cardiac arrest or ventricular fibrillation cardiac arrest. MEASUREMENTS AND MAIN RESULTS:In rats, cardiac output (20 ± 10 vs 45 ± 9 mL/min) and pH were lower and lactate higher (9.5 ± 1.0 vs 6.4 ± 1.3 mmol/L) after return of spontaneous circulation from ventricular fibrillation cardiac arrest versus asphyxial cardiac arrest (all p < 0.01). Asphyxial cardiac arrest resulted in greater early neurologic deficits, 7-day neuronal loss, and reduced freezing time (memory) after conditioned fear (all p < 0.05). Brain antioxidant reserves were more depleted following asphyxial cardiac arrest. In adjusted analyses, human ventricular fibrillation cardiac arrest was associated with greater cardiovascular injury based on peak troponin (7.8 ng/mL [0.8-57 ng/mL] vs 0.3 ng/mL [0.0-1.5 ng/mL]) and ejection fraction by echocardiography (20% vs 55%; all p < 0.0001), whereas asphyxial cardiac arrest was associated with worse early neurologic injury and poor functional outcome at hospital discharge (n = 46 [18%] vs 102 [44%]; p < 0.0001). Most ventricular fibrillation cardiac arrest deaths (54%) were the result of cardiovascular instability, whereas most asphyxial cardiac arrest deaths (75%) resulted from neurologic injury (p < 0.0001). CONCLUSIONS:In transcending rat and human studies, we find a consistent phenotype of heart and brain injury after cardiac arrest based on etiology: ventricular fibrillation cardiac arrest produces worse cardiovascular dysfunction, whereas asphyxial cardiac arrest produces worsened neurologic injury associated with greater oxidative stress.

Project description:ImportanceMany children with return of spontaneous circulation (ROSC) following cardiac arrest (CA) experience acute kidney injury (AKI). The impact of therapeutic hypothermia on the epidemiology of post-CA AKI in children has not been fully investigated.ObjectiveThe study aims were to: 1) describe the prevalence of severe AKI in comatose children following out-of-hospital CA (OHCA), 2) identify risk factors for severe AKI, 3) evaluate the impact of therapeutic hypothermia on the prevalence of severe AKI, and 4) evaluate the association of severe AKI with survival and functional outcomes.DesignA post hoc secondary analysis of data from the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital (THAPCA-OH) trial.SettingThirty-six pediatric intensive care units in the United States and Canada.ParticipantsOf 282 eligible subjects with an initial creatinine obtained within 24 h of randomization, 148 were randomized to therapeutic hypothermia and 134 were randomized to therapeutic normothermia.Main outcomes and measuresPrimary outcome was prevalence of severe AKI, as defined by stage 2 and 3 Kidney Disease Improving Global Outcomes (KDIGO) consensus definition; secondary outcome was survival with a favorable neurobehavioral outcome. For this study, risk factors and outcomes were compared between those with/without severe AKI.ResultsOf the 282 subjects enrolled, 180 (64%) developed AKI of which 117 (41% of all enrolled) developed severe AKI. Multivariable modeling found younger age, longer duration of chest compressions, higher lactate level at time of temperature intervention and higher number of vasoactive agents through day 1 of intervention associated with severe AKI. There was no difference in severe AKI between therapeutic hypothermia (39.9%) and therapeutic normothermia (43.3%) groups (p = 0.629). Survival was lower in those with severe AKI at 28 days (21% vs no severe AKI 49%, p < 0.001) and 12 months (21% vs no severe AKI 42%, p < 0.001). One year survival with favorable functional outcome was lower in those with severe AKI.Conclusions and relevanceSevere AKI occurs frequently in children with ROSC after OHCA, especially in younger children and those with higher initial lactates and hemodynamic support. Severe AKI was associated with worse survival and functional outcome. Therapeutic hypothermia did not reduce the incidence of severe AKI.

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Characterization of mitochondrial injury after cardiac arrest (COMICA).

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Characterization of mitochondrial injury after cardiac arrest (COMICA).

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