RESUMO
It has been reported that valproic acid (VPA) combined with therapeutic hypothermia can improve survival and neurologic outcomes in a rat asphyxial cardiac arrest model. However, neuroprotective mechanisms of such combined treatment of valproic acid with hypothermia remains unclear. We hypothesized that epigenetic regulation of HSP70 by histone acetylation could increase HSP70-mediated neuroprotection suppressed under hypothermia. Male Sprague-Dawley rats that achieved return of spontaneous circulation (ROSC) from asphyxial cardiac arrest were randomized to four groups: normothermia (37°C ± 1°C), hypothermia (33°C ± 1°C), normothermia + VPA (300 mg/kg IV initiated 5 minutes post-ROSC and infused over 20 min), and hypothermia + VPA. Three hours after ROSC, acetyl-histone H3 was highly expressed in VPA-administered groups (normothermia + VPA, hypothermia + VPA). Four hours after ROSC, HSP70 mRNA expression levels were significantly higher in normothermic groups (normothermia, normothermia + VPA) than in hypothermic groups (hypothermia, hypothermia + VPA). The hypothermia + VPA group showed significantly higher HSP70 mRNA expression than the hypothermia group. Similarly, at five hours after ROSC, HSP70 protein levels were significantly higher in normothermic groups than in hypothermic groups. HSP70 levels were significantly higher in the hypothermia + VPA group than in the hypothermia group. Only the hypothermia + VPA group showed significantly attenuated cleaved caspase-9 levels than the normothermia group. Hypothermia can attenuate the expression of HSP70 at transcriptional level. However, VPA administration can induce hyperacetylation of histone H3, leading to epigenetic transcriptional activation of HSP70 even in a hypothermic status. Combining VPA treatment with hypothermia may compensate for reduced activation of HSP70-mediated anti-apoptotic pathway.
Assuntos
Asfixia/terapia , Proteínas de Choque Térmico HSP70/metabolismo , Parada Cardíaca/terapia , Hipotermia Induzida/métodos , Neuroproteção , Ácido Valproico/uso terapêutico , Acetilação , Animais , Asfixia/tratamento farmacológico , Asfixia/metabolismo , Terapia Combinada , Modelos Animais de Doenças , Parada Cardíaca/tratamento farmacológico , Parada Cardíaca/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: To evaluate the associations between glycated hemoglobin (HbA1c) at admission and 6-month mortality and outcomes after out-of-hospital cardiac arrest (OHCA) treated by hypothermic targeted temperature management (TTM). METHODS: This single-center retrospective cohort study included adult OHCA survivors who underwent hypothermic TTM from December 2011 to December 2019. High HbA1c at admission was defined as a level higher than 6%. Poor neurological outcomes were defined as cerebral performance category scores of 3-5. The primary outcome was 6-month mortality. The secondary outcome was the 6-month neurological outcome. Descriptive statistics, log-rank tests, and multivariable regression modeling were used for data analysis. RESULTS: Of the 302 patients included in the final analysis, 102 patients (33.8%) had HbA1c levels higher than 6%. The high HbA1c group had significantly worse 6-month survival (12.7% vs. 37.5%, p < 0.001) and 6-month outcomes (89.2% vs. 73.0%, p = 0.001) than the non-high HbA1c group. Kaplan-Meier analysis and the log-rank test showed that the survival time was significantly shorter in the patients with HbA1c > 6% than in those with HbA1c ≤6%. In the multivariable logistic regression analysis, HbA1c > 6% was independently associated with 6-month mortality (OR 5.85, 95% CI 2.26-15.12, p < 0.001) and poor outcomes (OR 4.18, 95% CI 1.41-12.40, p < 0.001). CONCLUSIONS: This study showed that HbA1c higher than 6% at admission was associated with increased 6-month mortality and poor outcomes in OHCA survivors treated with hypothermic TTM. Poor long-term glycemic management may have prognostic significance after cardiac arrest.
Assuntos
Hemoglobinas Glicadas/análise , Parada Cardíaca Extra-Hospitalar/mortalidade , Idoso , Glicemia/análise , Estudos de Coortes , Feminino , Humanos , Hipotermia Induzida , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia/epidemiologia , Estudos RetrospectivosRESUMO
OBJECTIVES: The aim of this study was to evaluate the prognostic performance of the peak amplitude of P25/30 cortical somatosensory evoked potentials in predicting nonawakening in targeted temperature management-treated cardiac arrest patients. DESIGN: Prospective analysis. SETTING: Four academic tertiary care hospitals. PATIENTS: Eighty-seven cardiac arrest survivors after targeted temperature management. INTERVENTIONS: Analysis of the amplitude of P25/30. MEASUREMENTS AND MAIN RESULTS: In all participants, somatosensory evoked potentials were recorded after rewarming, and bilaterally absent pupillary and corneal reflexes were evaluated at 72 hours after the return of spontaneous circulation. We analyzed the amplitudes of the N20 and P25/30 peaks and the N20-P25/30 complex in cortical somatosensory evoked potentials. Upon hospital discharge, 87 patients were dichotomized into the awakening and nonawakening groups. The lowest amplitudes of N20, P25/30, and N20-P25/30 in the awakening patients were 0.17, 0.45, and 0.73 µV, respectively, and these thresholds showed a sensitivity of 70.5% (95% CI, 54.8-83.2%), 86.4% (95% CI, 72.7-94.8%), and 75.0% (95% CI, 59.7-86.8%), respectively, for nonawakening. The area under the curve of the P25/30 amplitude was significantly higher than that of the N20 amplitude (0.955 [95% CI, 0.912-0.998] vs 0.894 [95% CI, 0.819-0.969]; p = 0.036) and was comparable with that of the N20-P25/30 amplitude (0.931 [95% CI, 0.873-0.989]). Additionally, adding resuscitation variables or an absent brainstem reflex to the P25/30 amplitude showed a trend toward improving prognostic performance compared with the use of other somatosensory evoked potential amplitudes (area under the curve, 0.958; 95% CI, 0.917-0.999 and area under the curve, 0.974; 95% CI, 0.914-0.996, respectively). CONCLUSIONS: Our results provide evidence that the absence of the P25/30 peak and a reduction in the P25/30 amplitude may be considered prognostic indicators in these patients.
Assuntos
Potenciais Somatossensoriais Evocados/fisiologia , Parada Cardíaca/fisiopatologia , Parada Cardíaca/terapia , Hipotermia Induzida/métodos , Vigília/fisiologia , Centros Médicos Acadêmicos , Adulto , Idoso , Piscadela/fisiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Reflexo Pupilar/fisiologia , Reaquecimento/métodosRESUMO
BACKGROUND: Paricalcitol is known to attenuate ischemic-reperfusion injury of various organs. However, it is not known whether paricalcitol prevents neuronal injury after global cerebral ischemia. The purpose of this study is to investigate the neuroprotective effect of paricalcitol in a rat model of transient global cerebral ischemia. METHODS: This is a prospective, randomized experimental study. Male Sprague-Dawley rats that survived 10 min of four-vessel occlusion were randomly assigned to two treatment groups: one group was treated with paricalcitol 1 µg/kg IP, and the other was given an equivalent volume of normal saline IP. Drugs were administered at 5 min, 1 day, 2 days, and 3 days after ischemia. Neurologic function was assessed at 2 h, 1 day, 2 days, 3 days, and 4 days after ischemia. We tested motor function 3 days after ischemia using the rotarod test. Also, we tested memory function 4 days after ischemia using the passive avoidance test. We assessed neuronal degeneration in the hippocampus of surviving rats 4 days after ischemia. RESULTS: Eight rats were allocated to each group. No significant differences were found between the groups in terms of survival rate, motor coordination, or memory function. The neurological function score 2-h post-ischemia was significantly higher in the paricalcitol group (p = 0.04). Neuronal degeneration was significantly less in the paricalcitol group compared with the control group (p = 0.01). CONCLUSIONS: Paricalcitol significantly attenuated neuronal injury in the hippocampus. Although motor coordination, memory function, and survival rate were not significantly improved by paricalcitol treatment in this study, paricalcitol remains a potential neuroprotective drug after global cerebral ischemia.
RESUMO
OBJECTIVES: The absence of N20 somatosensory evoked potential after cardiac arrest is related to poor outcome. However, discrimination between the low-amplitude and the absence of N20 is challenging. P25 and P30 are short-latency positive peaks with latencies between 25 and 30 ms following N20 (P25/30). P25/30 is evident even with an ambiguous N20 in patients with good outcome. Therefore, we evaluated the predictive value of P25/30 after cardiac arrest. DESIGN: A retrospective observational study. SETTING: University-affiliated hospital. SUBJECTS: Comatose survivors after out-of-hospital cardiac arrest treated by hypothermic targeted temperature management. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The specificity and the positive predictive value of P25/30 and N20 in predicting poor outcome were the same, showing a rate of 100%. The sensitivity of P25/30 in predicting poor outcome (90.12% [95% CI, 81.5-95.6%]) was higher than that of N20 (70.37% [95% CI, 59.2-80%]). Also, the negative predictive value of P25/30 in predicting poor outcome (81.4% [95% CI, 69.4-89.4%]) was higher than that of N20 (59.3% [95% CI, 51-67.1%]). The P25/30-based adjusted model showed a larger area under the curve (0.98 [95% CI, 0.95-1]) compared with the N20-based adjusted model (0.95 [95% CI, 0.91-0.98]) (p = 0.02). CONCLUSIONS: The absence of P25/30 is related to poor outcome with a higher sensitivity, negative predictive value than the absence of N20.
Assuntos
Lesões Encefálicas/etiologia , Encéfalo/fisiopatologia , Potenciais Somatossensoriais Evocados , Parada Cardíaca Extra-Hospitalar/complicações , Lesões Encefálicas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/diagnóstico , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: Neutrophil gelatinase-associated lipocalin (NGAL) is secreted by various tissues in pathologic states. Previous studies reported that post-cardiac arrest serum NGAL levels correlate with short-term neurologic outcomes and survival. The aim of this study was to examine the associations between NGAL levels post-cardiac arrest and long-term outcomes and survival. METHODS: This prospective observational study and retrospective review included adult out-of-hospital cardiac arrest survivors who were treated by hypothermia-targeted temperature management. Serum NGAL was assessed at 0, 24, 48, and 72h after return of spontaneous circulation. The primary outcome was poor outcome at six months after cardiac arrest, defined as cerebral performance category score of 3-5. The secondary outcome was six-month mortality. RESULTS: In total, 76 patients were analyzed. The patients with poor outcomes showed significantly higher NGAL levels at 24, 48 and 72h after cardiac arrest than the patients with good outcomes. Long-term survival rates were significantly lower in the high-NGAL group than in the low-NGAL group at each time point. Subgroup analysis of patients who survived 72h showed that only serum NGAL 72h after cardiac arrest had prognostic value for long-term outcomes (area under the receiver operating characteristic curve=0.72; p=0.02). CONCLUSIONS: Post-cardiac arrest serum NGAL is associated with long-term outcomes and survival; particularly, three days post-cardiac arrest is the optimal time point for predicting long-term outcomes. However, the predictive power of NGAL is unsatisfactory, and it should be regarded as an additional prognostic modality.