Neurological Impact of Slower Rewarming during Bypass Surgery in Infants.

BACKGROUND: Hypothermia is a neuroprotective strategy during cardiopulmonary bypass. Rewarming entailing a rapid rise in cerebral metabolism might lead to secondary neurological sequelae. In this pilot study, we aimed to validate the hypothesis that a slower rewarming rate would lower the risk of cerebral hypoxia and seizures in infants. METHODS: This is a prospective, clinical, single-center study. Infants undergoing cardiac surgery in hypothermia were rewarmed either according to the standard (+1°C in < 5 minutes) or a slow (+1°C in > 5-8 minutes) rewarming strategy. We monitored electrocortical activity via amplitude-integrated electroencephalography (aEEG) and cerebral oxygenation by near-infrared spectroscopy during and after surgery. RESULTS: Fifteen children in the standard rewarming group (age: 13 days [5-251]) were cooled down to 26.6°C (17.2-29.8) and compared with 17 children in the slow-rewarming group (age: 9 days [4-365]) with a minimal temperature of 25.7°C (20.1-31.4). All neonates in both groups (n = 19) exhibited suppressed patterns compared with 28% of the infants > 28 days (p < 0.05). During rewarming, only 26% of the children in the slow-rewarming group revealed suppressed aEEG traces (vs. 41%; p = 0.28). Cerebral oxygenation increased by a median of 3.5% in the slow-rewarming group versus 1.5% in the standard group (p = 0.9). Our slow-rewarming group revealed no aEEG evidence of any postoperative seizures (0 vs. 20%). CONCLUSION: These results might indicate that a slower rewarming rate after hypothermia causes less suppression of electrocortical activity and higher cerebral oxygenation during rewarming, which may imply a reduced risk of postoperative seizures.

Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model.

Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 µg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.

Early cerebral hypoxia in extremely preterm infants and neurodevelopmental impairment at 2 year of age: A post hoc analysis of the SafeBoosC II trial.

BACKGROUND: The SafeBoosC II, randomised clinical trial, showed that the burden of cerebral hypoxia was reduced with the combination of near infrared spectroscopy and a treatment guideline in extremely preterm infants during the first 72 hours after birth. We have previously reported that a high burden of cerebral hypoxia was associated with cerebral haemorrhage and EEG suppression towards the end of the 72-hour intervention period, regardless of allocation. In this study we describe the associations between the burden of cerebral hypoxia and the 2-year outcome. METHODS: Cerebral oxygenation was continuously monitored from 3 to 72 hours after birth in 166 extremely preterm infants. At 2 years of age 114 of 133 surviving children participated in the follow-up program: medical examination, Bayley II or III test and the parental Ages and Stages Questionnaire. The infants were classified according to the burden of hypoxia: within the first three quartiles (n = 86, low burden) or within in the 4th quartile (n = 28, high burden). All analyses were conducted post hoc. RESULTS: There were no statistically significant differences between the quantitative assessments of neurodevelopment in the groups of infants with the low burden of cerebral hypoxia versus the group of infants with the high burden of cerebral hypoxia. The infants in the high hypoxia burden group had a higher-though again not statistically significant-rate of cerebral palsy (OR 2.14 (0.33-13.78)) and severe developmental impairment (OR 4.74 (0.74-30.49). CONCLUSIONS: The burden of cerebral hypoxia was not significantly associated with impaired 2-year neurodevelopmental outcome in this post-hoc analysis of a feasibility trial.

Effective method of monitoring cerebral tissue oxygen saturation in cardiac surgery patients by combined use of tNIRS-1 and bispectral index.

To continuously and noninvasively monitor the cerebral tissue oxygen saturation (StO2) and hemoglobin concentration (gasHb) in cardiac surgery patients, a method combining the use of a cerebral tissue oximeter using near infrared time-resolved spectroscopy (tNIRS-1) and the bispectral index (BIS) was developed in this study. Moreover, the correlation between the estimated hemoglobin concentration (estHb), measured via tNIRS-1, and the hemoglobin concentration (gasHb), analyzed using a blood gas analyzer, were compared. The relationship between the BIS and gasHb was also examined. Through the comparison of BIS and StO2 (r1), and estHb and gasHb (r2), the correlation between the two was clarified with maximum r1 and r2 values of 0.617 and 0.946, respectively. The relationship between BIS and gasHb (r3), showed that there was a favorable correlation with a maximum r3 value of 0.969. There was also a continuous correlation between BIS and StO2 in patients undergoing cardiac surgery. In addition, a strong correlation was found between estHb and gasHb, and between BIS and gasHb. It was therefore concluded that the combined use of BIS and tNIRS-1 is useful to evaluate cerebral hypoxia, allowing for quick response to cerebral hypoxia and reduction of hemoglobin concentration during the operation.

Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model.

Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-κB p65, neuronal nitric oxide synthase (nNOS), TNF-α, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-κB p65, nNOS, TNF-α and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia.

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.

Repeated hypoxia exposure induces cognitive dysfunction, brain inflammation, and amyloidß/p-Tau accumulation through reduced brain O-GlcNAcylation in zebrafish.

Repetitive hypoxia (RH) exposure affects the initiation and progression of cognitive dysfunction, but little is known about the mechanisms of hypoxic brain damage. In this study, we show that sublethal RH increased anxiety, impaired learning and memory (L/M), and triggered downregulation of brain levels of glucose and several glucose metabolites in zebrafish, and that supplementation of glucose or glucosamine (GlcN) restored RH-induced L/M impairment. Fear conditioning (FC)-induced brain activation of and PKA/CREB signaling was abrogated by RH, and this effect was reversed by GlcN supplementation. RH was associated with decreased brain O-GlcNAcylation and an increased O-GlcNAcase (OGA) level. RH increased brain inflammation and p-Tau and amyloid ß accumulation, and these effects were suppressed by GlcN. Our observations collectively suggest that changes in O-GlcNAc flux during hypoxic exposure could be an important causal factor for neurodegeneration, and that supplementation of the HBP/O-GlcNAc flux may be a potential novel therapeutic or preventive target for addressing hypoxic brain damage.

Cerebral Oxygenation and Perfusion when Positioning Preterm Infants: Clinical Implications.

OBJECTIVES: To evaluate cerebral tissue oxygenation (cTOI) and cerebral perfusion in preterm infants in supine vs prone positions. STUDY DESIGN: Sixty preterm infants, born before 32 weeks of gestation, were enrolled; 30 had bronchopulmonary dysplasia (BPD, defined as the need for respiratory support and/or supplemental oxygen at 36 weeks of postmenstrual age). Cerebral perfusion, cTOI, and polysomnography were measured in both the supine and prone position with the initial position being randomized. Infants with a major intraventricular hemorrhage or major congenital abnormality were excluded. RESULTS: Cerebral perfusion was unaffected by position or BPD status. In the BPD group, the mean cTOI was higher in the prone position compared with the supine position by a difference of 3.27% (P = .03; 95% CI 6.28-0.25) with no difference seen in the no-BPD group. For the BPD group, the burden of cerebral hypoxemia (cumulative time spent with cTOI <55%) was significantly lower in the prone position (23%) compared with the supine position (29%) (P < .001). In those without BPD, position had no effect on cTOI. CONCLUSIONS: In preterm infants with BPD, the prone position improved cerebral oxygenation and reduced cerebral hypoxemia. These findings may have implications for positioning practices. Further research will establish the impact of position on short- and long-term developmental outcomes.

Recombinant Human Growth Hormone Activates Neuroprotective Growth Factors in Hypoxic Brain Injury in Neonatal Mice.

Perinatal hypoxia severely disrupts cerebral metabolic and maturational programs beyond apoptotic cell death. Antiapoptotic treatments such as erythropoietin are suggested to improve outcomes in hypoxic brain injury; however, the results are controversial. We analyzed the neuroprotective effects of recombinant human growth hormone (rhGH) on regenerative mechanisms in the hypoxic developing mouse brain in comparison to controls. Using an established model of neonatal acute hypoxia (8% O2, 6 hours), P7 mice were treated intraperitoneally with rhGH (4000 µg/kg) 0, 12, and 24 hours after hypoxic exposure. After a regeneration period of 48 hours, expression of hypoxia-inducible neurotrophic factors (erythropoietin [EPO], vascular endothelial growth factor A [VEGF-A], insulin-like growth factors 1 and 2 [IGF-1/-2], IGF binding proteins) and proinflammatory markers was analyzed. In vitro experiments were performed using primary mouse cortical neurons (E14, DIV6). rhGH increased neuronal gene expression of EPO, IGF-1, and VEGF (P < .05) in vitro and diminished apoptosis of hypoxic neurons in a dose-dependent manner. In the developing brain, rhGH treatment led to a notable reduction of apoptosis in the subventricular zone and hippocampus (P < .05), abolished hypoxia-induced downregulation of IGF-1/IGF-2 expression (P < .05), and led to a significant accumulation of endogenous EPO protein and anti-inflammatory effects through modulation of interleukin-1ß and tumor necrosis factor α signaling as well as upregulation of cerebral phosphorylated extracellularly regulated kinase 1/2 levels (ERK1/2). Indicating stabilizing effects on the blood-brain barrier (BBB), rhGH significantly modified cerebrovascular occludin expression. Thus, we conclude that rhGH mediates neuroprotective effects by the activation of endogenous neurotrophic growth factors and BBB stabilization. In addition, the modification of ERK1/2 pathways is involved in neuroprotective actions of rhGH. The present study adds further evidence that pharmacologic activation of neurotrophic growth factors may be a promising target for neonatal neuroprotection.

Combined transplantation of neural stem cells and bone marrow mesenchymal stem cells promotes neuronal cell survival to alleviate brain damage after cardiac arrest via microRNA-133b incorporated in extracellular vesicles.

Neural stem cell (NSC) transplantation has prevailed as a promising protective strategy for cardiac arrest (CA)-induced brain damage. Surprisingly, the poor survival of neuronal cells in severe hypoxic condition restricts the utilization of this cell-based therapy. Extracellular vesicles (EVs) transfer microRNAs (miRNAs) between cells are validated as the mode for the release of several therapeutic molecules. The current study reports that the bone marrow mesenchymal stem cells (BMSCs) interact with NSCs via EVs thereby affecting the survival of neuronal cells. Hypoxic injury models of neuronal cells were established using cobalt chloride, followed by co-culture with BMSCs and NSCs alone or in combination. BMSCs combined with NSCs elicited as a superior protocol to stimulate neuronal cell survival. BMSCs-derived EVs could protect neuronal cells against hypoxic injury. Silencing of miR-133b incorporated in BMSCs-derived EVs could decrease the cell viability and the number of NeuN-positive cells and increase the apoptosis in the CA rat model. BMSCs-derived EVs could transfer miR-133b to neuronal cells to activate the AKT-GSK-3ß-WNT-3 signaling pathway by targeting JAK1. Our study demonstrates that NSCs promotes the release of miR-133b from BMSCs-derived EVs to promote neuronal cell survival, representing a potential therapeutic strategy for the treatment of CA-induced brain damage.

Metformin ameliorates brain damage caused by cardiopulmonary resuscitation via targeting endoplasmic reticulum stress-related proteins GRP78 and XBP1.

Cerebral damage after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is a primary cause of death. Endoplasmic reticulum stress (ERS) is very important during these situations. This study aimed to explore the role of metformin in protecting brain endoplasmic reticulum post CA/CPR. Male SD rats (n = 132) were treated with 6-min CA-posted asphyxia and sham surgery. Before CA/CPR, metformin (200 mg/kg/day) or a vehicle (0.9% saline) were administered randomly for two weeks. The neurological deficit scores were assessed 24 h, 48 h, 72 h, and 7 days after CA/CPR, and the rat brains were analyzed by Western blotting and qRT-PCR. Apoptosis was detected by the TUNEL assay according to the mitochondrial membrane potential (MMP). Oxidative stress and ERS-related protein expression were also investigated. The Western blotting and qRT-PCR results revealed that the resuscitated animals had time-dependent elevated GRP78 and XBP1 levels compared with the sham operative rats. Moreover, our results showed that the rats treated with metformin had increased neurological deficit scores (NDS), an improved seven-day survival rate, decreased cell apoptosis within the hippocampus CA1 area, and less oxidative stress compared with the CA/CPR group. Furthermore, metformin inhibited the mRNA and protein expressions of glucose-regulated protein 78 (GRP78) and X-box binding protein 1 (XBP1) in the CA/CPR rat model. We confirmed that CA/CPR can induce ERS-related apoptosis and oxidative stress in the brain; moreover, inhibiting ERS-related proteins GRP78 and XBP1 with metformin might attenuate cerebral injury post CA/CPR.

Astrocytic Yes-associated protein attenuates cerebral ischemia-induced brain injury by regulating signal transducer and activator of transcription 3 signaling.

Astrocytic Yes-associated protein (YAP) has been implicated in astrocytic proliferation and differentiation in the developing neocortex. However, the role of astrocytic YAP in diseases of the nervous system remains poorly understood. Here, we hypothesized that astrocytic YAP exerted a neuroprotective effect against cerebral ischemic injury in rats by regulating signal transducer and activator of transcription 3 (STAT3) signaling. In this study, we investigated whether the expression of nuclear YAP in the astrocytes of rats increased significantly after middle cerebral artery occlusion (MCAO) and its effect on cerebral ischemic injury. We used XMU-MP-1 to trigger localization of YAP into the nucleus and found that XMU-MP-1 treatment decreased ischemia/stroke-induced brain injury including reduced neuronal death and reactive astrogliosis, and extenuated release of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanically, XMU-MP-1 treatment suppressed the expression of phospho-STAT3 (P-STAT3). We established an in-vitro oxygen-glucose deprivation/reperfusion (OGD/R) model to simulate an ischemic condition and further explore the function of astrocytic YAP. We found that nuclear translocation of astrocytic YAP in rats could improve cell vitality, decrease the release of inflammatory cytokines and reduce the expression of P-STAT3 in vitro. In contrast, we also found that inhibition of YAP by verteporfin further aggravated the injury induced by OGD/R via STAT3 signaling. In summary, our results showed that nuclear localization of astrocytic YAP exerted a neuroprotective effect after cerebral ischemic injury in rats via inhibition of the STAT3 signaling.

Adenosine, Lidocaine, and Magnesium Support a High Flow, Hypotensive, Vasodilatory State With Improved Oxygen Delivery and Cerebral Protection in a Pig Model of Noncompressible Hemorrhage.

BACKGROUND: Noncompressible hemorrhage is the leading cause of preventable death in military and civilian trauma. Our aim was to examine the effect of adenosine, lidocaine, and magnesium (Mg2+; ALM) on cardiovascular and cerebral function in a porcine hepatic hemorrhage model. MATERIALS AND METHODS: Pigs (59.1 ± 0.34 kg) were anesthetized, instrumented, and randomly assigned into sham (n = 6), saline controls (n = 10) or ALM (n = 10) groups before laparoscopic liver resection. After 30 min, groups received 4 mL/kg 3% NaCl ± ALM bolus (Phase 1) followed 60 min later with 3 mL/kg/h 0.9% NaCl ± ALM drip (4 h; Phase 2), then transfusion. Hemodynamics, carotid artery flow, and intracranial pressure were measured continuously. Microdialysis samples were analyzed for metabolites. RESULTS: Saline controls had 20% mortality (mean survival time: 307 ± 38 min) with no ALM deaths over 6 h. Bolus administration increased mean arterial pressure (MAP) in both groups, and drip led to further increases to 62 ± 10 mmHg in controls compared with a steady fall to 47 ± 8 mmHg in ALM group at 240 min. The lower MAP was associated with a dramatic fall in systemic vascular resistance and improved oxygen delivery. ALM drip significantly increased cardiac output and stroke volume with lower dP/dtMin, indicating a less stiff heart. ALM drip also significantly decreased cerebral perfusion pressure, reduced cerebral oxygen consumption (28%), and reduced brain glycerol (60%), lactate (47%), and relative expression of hypoxia-inducible factor (38%) compared with saline controls. CONCLUSIONS: ALM therapy improved cardiac function and oxygen delivery by lowering systemic vascular resistance after noncompressible hemorrhage. ALM also appeared to protect the brain at hypotensive MAPs with significantly lower cerebral perfusion pressure, lower O2 consumption, and significantly lower cortical lactate and glycerol levels compared to saline controls.

Midazolam contributes to neuroprotection against hypoxia/reoxygenation-induced brain injury in neonatal rats via regulation of EAAT2.

Excitotoxicity is one of the main mechanisms related to hypoxia/reoxygenation (H/R) injury. Excitatory amino acid transporter (EAAT)2 mainly distributes on astrocytes and plays an important role on glutamate reuptake and glutamate homeostasis. Midazolam has a neuroprotective effect in some neuropathological conditions. The present study aimed to detect the role of EAAT2 in the neuroprotective effect of midazolam in neonatal rat brain subjected to H/R. Pretreatment with midazolam reversed H/R-induced apoptosis and downregulation of EAAT2 mRNA and protein expression in the hippocampus. Pretreatment with dihydrokainic acid (a selective inhibitor of EAAT2) exacerbated apoptosis, and thus inhibited the neuroprotective effect of midazolam against H/R injury. We demonstrated for the first time that dysregulation of EAAT2 expression may be related to the neural injury induced by H/R in rat pups, and pretreatment with midazolam attenuated apoptosis and improved learning and memory partly due to regulating EAAT2 expression.

Effects of regional body temperature variation during asphyxial cardiac arrest on mortality and brain damage in a rat model.

To date, hypothermia has focused on improving rates of resuscitation to increase survival in patients sustaining cardiac arrest (CA). Towards this end, the role of body temperature in neuronal damage or death during CA needs to be determined. However, few studies have investigated the effect of regional temperature variation on survival rate and neurological outcomes. In this study, adult male rats (12 week-old) were used under the following four conditions: (i) whole-body normothermia (37 ± 0.5 °C) plus (+) no asphyxial CA, (ii) whole-body normothermia + CA, (iii) whole-body hypothermia (33 ± 0.5 °C)+CA, (iv) body hypothermia/brain normothermia + CA, and (v) brain hypothermia/body normothermia + CA. The survival rate after resuscitation was significantly elevated in groups exposed to whole-body hypothermia plus CA and body hypothermia/brain normothermia plus CA, but not in groups exposed to whole-body normothermia combined with CA and brain hypothermia/body normothermia plus CA. However, the group exposed to hypothermia/brain normothermia combined with CA exhibited higher neuroprotective effects against asphyxial CA injury, i.e. improved neurological deficit and neuronal death in the hippocampus compared with those involving whole-body normothermia combined with CA. In addition, neurological deficit and neuronal death in the group of rat exposed to brain hypothermia/body normothermia and CA were similar to those in the rats subjected to whole-body normothermia and CA. In brief, only brain hypothermia during CA was not associated with effective survival rate, neurological function or neuronal protection compared with those under body (but not brain) hypothermia during CA. Our present study suggests that regional temperature in patients during CA significantly affects the outcomes associated with survival rate and neurological recovery.

HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage.

The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na+/Ca+ exchanger isoform 3 (ncx3) after stroke are still unknown. Overexpression or knocking-down of HDAC4/HDAC5 down-regulates or increases, respectively, NCX3 mRNA and protein. Likewise, MC1568 (class IIa HDACs inhibitor), but not MS-275 (class I HDACs inhibitor) increased NCX3 promoter activity, gene and protein expression. Furthermore, HDAC4 and HDAC5 physically interacted with the transcription factor downstream regulatory element antagonist modulator (DREAM). As MC1568, DREAM knocking-down prevented HDAC4 and HDAC5 recruitment to the ncx3 promoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation of ncx3 promoter. Conversely, the tMCAO-induced NCX3 reduction was prevented by intracerebroventricular injection of siDREAM, siHDAC4, and siHDAC5. Notably, MC1568 prevented oxygen glucose deprivation plus reoxygenation and tMCAO-induced neuronal damage, whereas its neuroprotective effect was abolished by ncx3 knockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulates ncx3 gene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.

[Target temperature in post-cardiac-arrest complex intensive care: arguments for mild therapeutic hypothermia]. / Célhomérséklet a tartós újraélesztés utáni komplex intenzív kezelés során. Állásfoglalás az enyhe terápiás hypothermia mellett.

Long term survival of successfully resuscitated patients is primarily determined by their post-cardiac arrest neurological function. If the patient undergoes a long-term resuscitation or remains comatose as part of the post-cardiac arrest syndrome (PCAS), organ-specific intensive care is urged to aim hemodynamic stabilisation, normalisation of organ perfusion and prevention of injuries at cellular level. One of the basic measures of PCAS intensive care is to prevent hypoxic brain injury by mild therapeutic hypothermia (THT). The physiological changes of the human body at hypothermic conditions require high level monitoring and specially focused intensive care limiting its implementation. The multicentric, controlled, randomized targeted temperature management (TTM) trial published in 2013 compared the TTM against the THT in the treatment of PCAS patients. The equal outcome of the 2 methods has partly changed the practice of the intensivists in the treatment of such patients. This manuscript gives the pros and cons for each therapeutic method in post-resuscitation therapy. Nevertheless, the author shows the possible implementations and the DRG (diagnosis-related group) reimbursement of the method in Hungary. Orv Hetil. 2019; 160(46): 1840-1844.

Targeted Temperature Management and Postcardiac arrest Care.

Despite recent advances, care of the post-cardiac arrest patient remains a challenge. In this article, the authors discuss an approach to the initial care of post-cardiac arrest patients with particular focus on targeted temperature management (TTM). The article starts with history, physiologic rationale, and the major randomized controlled trials that have shaped guidelines for post-cardiac arrest care. It also reviews controversial topics, including TTM for nonshockable rhythms, TTM dose, and surface versus endovascular cooling. The article concludes with a brief review of other key aspects of post-arrest care: coronary angiography, hemodynamic optimization, ventilator management, and prognostication.