Despite extensive research on neuroimaging correlates of human brain aging, there is little mechanistic insight into how they are linked to loss of brain function. Previous studies on the role of cerebral blood flow (CBF) in supporting brain function have focused on delivery of nutrients, namely oxygen and glucose. However, CBF is required also to clear the byproducts of energy metabolism, namely CO2 and protons. With the goal of determining whether age-associated reduction in regional CBF may lead to abnormal brain partial pressure of carbon dioxide (pCO2) and pH levels that are sufficient to alter brain activity and cognitive function, we applied a recently introduced homeostatic modeling of nutrients and waste products to human neuroimaging PET data acquired in young and older adults (Goyal et al. in Cell Metab 26(2):353-360, 2017). Our results demonstrate that age-associated reductions in CBF, in the presence of virtually unaltered oxygen consumption rates, show concurrent regional age-associated increases in pCO2 and associated pH acid-shifts of possible functional relevance. We conclude that the implications of altered vascular health in older adults needs to be revisited in light of its central role in removing waste products from energy metabolism at resting state and, in future studies, during external stimulations.
- MeSH
- Adult MeSH
- Energy Metabolism * MeSH
- Hydrogen-Ion Concentration MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Brain * metabolism MeSH
- Cerebrovascular Circulation * physiology MeSH
- Carbon Dioxide * metabolism MeSH
- Positron-Emission Tomography * MeSH
- Aged MeSH
- Oxygen Consumption MeSH
- Aging * metabolism physiology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Introduction and Importance: Some experimental studies on brain injury associated with traumatic brain injury (TBI) and hypoxic-ischaemic encephalopathy (HIE) reveal a positive effect of hyperbaric oxygen therapy (HBOT). However, in clinical medicine, most of the scientific evidence available in the current literature relates only to TBI. Methods: The primary objective is to empirically assess the efficacy of HBOT in mitigating the symptoms of disability associated with brain injury in children, with a view to elucidating its therapeutic potential and clinical benefits. Outcomes: A total of 21 patients have been treated with HBOT. The mean age was 6±4.6 years. There were 12 cases (57%) of TBI, 8 cases (38%) of HIE and 1 case (5%) of ischaemic stroke. The mean initial Glasgow Coma Scale (GCS) at hospital admission immediately after accident was 3.3±0.9. The mean time from injury to HBOT was 5.2 ± 3.8 weeks. The mean number of HBOT exposures was 10±4.3. The mean GCS pre-HBOT was 10.7±3.7 and 12.3±3.4 (p=0.004) after post-HBOT, respectively. The mean Glasgow Outcome Scale (GOS) was 3.3±0.8 pre-HBOT, and 3.9±1.1 (p<0.001) after post-HBOT, respectively. Eighteen cases were included in response to HBOT assessment. Six cases (33%) were evaluated as large clinically significant response (CSR), 7 cases (39%) were evaluated as partial response with minimally important difference (MID). Five cases (28%) were evaluated as non-response. The results showed better response to HBOT in cases of starting HBOT up to 4 weeks (p=0.02) after the injury. There was no serious HBOT-related complication or injury. Conclusion: Results of our study demonstrate both clinical and statistically significant patient response to HBOT. Our data also suggest that the earlier HBOT started after diagnosis up to 4 weeks, the more pronounced patients' response to HBOT was achieved. The provision of HBOT to pediatric patients is feasible in large regional hyperbaric centers.
- MeSH
- Child MeSH
- Glasgow Coma Scale * MeSH
- Glasgow Outcome Scale MeSH
- Hyperbaric Oxygenation * methods MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Hypoxia-Ischemia, Brain * therapy MeSH
- Brain Injuries therapy MeSH
- Child, Preschool MeSH
- Retrospective Studies MeSH
- Brain Injuries, Traumatic therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
The fetus develops normally in a hypoxic environment but exaggerated hypoxia late in pregnancy is a worrisome sign often observed in hypertensive disorders of pregnancy, placental insufficiency, or fetal growth restriction (FGR). Serial fetal biometry and the cerebroplacental ratio (CPR, calculated as the middle cerebral artery [MCA] / the umbilical artery [UmbA] pulsatility indices [PI]), are commonly used to indicate fetal "brain sparing" resulting from exaggerated fetal hypoxia. But unclear is the extent to which a low CPR indicates pathology or is a physiological response for maintaining cerebral blood flow. We studied 31 appropriate for gestational age (AGA) pregnancies at low (LA, 1670 m) or high (HA, 2879 m) altitude, given the chronic hypoxia imposed by HA residence, and 54 LA women with a clinical diagnosis of FGR. At week 34, the MCA PI was lower in the LA-FGR than the LA-AGA group but lower still in the HA-AGA compared to either LA groups due to a trend toward higher end-diastolic velocity (EDV). We concluded that the lower MCA PI was likely due to greater cerebral vasodilation in the HA AGA group and an indication of physiological versus pathological fetal hypoxia. Future reporting of serial MCA and UmbA values and their determinants along with the CPR could improve our ability to distinguish between physiological and pathological fetal brain sparing. Keywords: Birth weight, Cerebroplacental ratio, Fetal physiology, HDP, High altitude.
- MeSH
- Middle Cerebral Artery * diagnostic imaging physiopathology MeSH
- Umbilical Arteries diagnostic imaging physiopathology MeSH
- Adult MeSH
- Fetal Hypoxia * physiopathology MeSH
- Hypoxia physiopathology MeSH
- Humans MeSH
- Brain physiopathology blood supply diagnostic imaging MeSH
- Cerebrovascular Circulation physiology MeSH
- Altitude MeSH
- Fetal Growth Retardation * physiopathology MeSH
- Pregnancy MeSH
- Ultrasonography, Prenatal methods MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: The initial rhythm is a known predictor of survival in extracorporeal cardiopulmonary resuscitation (ECPR) patients. However, the effect of the rhythm at hospital admission on outcomes in these patients is less clear. METHODS: This observational, single-center study assessed the influence of the rhythm at hospital admission on 30-day survival and neurological outcomes at discharge in patients who underwent ECPR for out-of-hospital cardiac arrest (OHCA). RESULTS: Between January 2012 and December 2023, 1,219 OHCA patients were admitted, and 210 received ECPR. Of these, 196 patients were analyzed. The average age was 52.9 years (±13), with 80.6 % male. The median time to ECPR initiation was 61 min (IQR 54-72). Patients with ventricular fibrillation as both the initial and admission rhythm had the highest 30-day survival rate (52 %: 35/67), while those with asystole in both instances had the lowest (6 %: 1/17, log-rank p < 0.00001). After adjusting for age, sex, initial rhythm, resuscitation time, location, bystander, and witnessed status, asystole at admission was linked to higher 30-day mortality (OR 4.03, 95 % CI 1.49-12.38, p = 0.009) and worse neurological outcomes (Cerebral Performance Category 3-5) at discharge (OR 4.61, 95 % CI 1.49-17.62, p = 0.013). CONCLUSIONS: The rhythm at hospital admission affects ECPR outcomes. Patients presenting with and maintaining ventricular fibrillation have a higher chance of favorable neurological survival, whereas those presenting with or converting to asystole have poor outcomes. The rhythm at hospital admission appears to be a valuable criterion for deciding on ECPR initiation.
- MeSH
- Adult MeSH
- Ventricular Fibrillation therapy mortality complications MeSH
- Hospitalization statistics & numerical data MeSH
- Cardiopulmonary Resuscitation * methods statistics & numerical data MeSH
- Middle Aged MeSH
- Humans MeSH
- Extracorporeal Membrane Oxygenation * methods statistics & numerical data MeSH
- Survival Rate trends MeSH
- Patient Admission statistics & numerical data MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Heart Rate physiology MeSH
- Out-of-Hospital Cardiac Arrest * therapy mortality MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
RATIONALE: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. AIMS: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. METHODS AND DESIGN: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. STUDY OUTCOMES: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. DISCUSSION: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.
- MeSH
- Endovascular Procedures * methods MeSH
- Ischemic Stroke * complications diagnosis MeSH
- Brain Ischemia * complications MeSH
- Clinical Trials, Phase II as Topic MeSH
- Quality of Life MeSH
- Oxygen therapeutic use MeSH
- Humans MeSH
- Multicenter Studies as Topic MeSH
- Thrombectomy methods MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial Protocol MeSH
BACKGROUND: We aimed to estimate the effect of extracorporeal cardiopulmonary resuscitation (ECPR) on neurological outcome and mortality, when compared to conventional cardiopulmonary resuscitation (CCPR), using an individual patient data meta-analysis (IPDMA). METHODS: A systematic literature search was performed up to the 20th of October 2022 in the PubMed, EMBASE and CENTRAL databases. For observational studies with unmatched populations, a propensity score including age, location of arrest and initial rhythm was used to match ECPR and CCPR patients in a 1:1 ratio. The primary and secondary outcomes were unfavorable neurological outcome (Cerebral Performance Category of 3-5) and mortality, respectively, which were both collected at different time-points. RESULTS: Data from 17 studies, including 2064 matched cardiac arrest (CA) patients (1031 ECPR and 1033 CCPR cases) were included. In comparison to CCPR, ECPR was associated with a decreased odds of unfavorable neurological outcome (847, 82.2% vs. 897, 86.8% - OR 0.68 [95%CI 0.53-0.87]; p = 0.002) and death (803, 77.9% vs. 860, 83.3% - OR 0.68 [95%CI 0.54-0.86]; p = 0.001). These results were consistent across most of the prespecified subgroups. Moreover, the odds of both unfavorable neurological outcome and mortality were significantly influenced by initial rhythm, cause of arrest and combinations of lactate levels on admission and duration of resuscitation. CONCLUSIONS: This IPDMA showed that ECPR was associated with significantly lower rates of unfavorable neurological outcome and mortality in refractory CA. The overall effect could be influenced by CA characteristics and the severity of the initial injury.
BACKGROUND: Cerebral perfusion may change depending on arterial cannulation site and may affect the incidence of neurologic adverse events in post-cardiotomy extracorporeal life support (ECLS). The current study compares patients' neurologic outcomes with three commonly used arterial cannulation strategies (aortic vs. subclavian/axillary vs. femoral artery) to evaluate if each ECLS configuration is associated with different rates of neurologic complications. METHODS: This retrospective, multicenter (34 centers), observational study included adults requiring post-cardiotomy ECLS between January 2000 and December 2020 present in the Post-Cardiotomy Extracorporeal Life Support (PELS) Study database. Patients with Aortic, Subclavian/Axillary and Femoral cannulation were compared on the incidence of a composite neurological end-point (ischemic stroke, cerebral hemorrhage, brain edema). Secondary outcomes were overall in-hospital mortality, neurologic complications as cause of in-hospital death, and post-operative minor neurologic complications (seizures). Association between cannulation and neurological outcomes were investigated through linear mixed-effects models. RESULTS: This study included 1897 patients comprising 26.5% Aortic (n = 503), 20.9% Subclavian/Axillary (n = 397) and 52.6% Femoral (n = 997) cannulations. The Subclavian/Axillary group featured a more frequent history of hypertension, smoking, diabetes, previous myocardial infarction, dialysis, peripheral artery disease and previous stroke. Neuro-monitoring was used infrequently in all groups. Major neurologic complications were more frequent in Subclavian/Axillary (Aortic: n = 79, 15.8%; Subclavian/Axillary: n = 78, 19.6%; Femoral: n = 118, 11.9%; p < 0.001) also after mixed-effects model adjustment (OR 1.53 [95% CI 1.02-2.31], p = 0.041). Seizures were more common in Subclavian/Axillary (n = 13, 3.4%) than Aortic (n = 9, 1.8%) and Femoral cannulation (n = 12, 1.3%, p = 0.036). In-hospital mortality was higher after Aortic cannulation (Aortic: n = 344, 68.4%, Subclavian/Axillary: n = 223, 56.2%, Femoral: n = 587, 58.9%, p < 0.001), as shown by Kaplan-Meier curves. Anyhow, neurologic cause of death (Aortic: n = 12, 3.9%, Subclavian/Axillary: n = 14, 6.6%, Femoral: n = 28, 5.0%, p = 0.433) was similar. CONCLUSIONS: In this analysis of the PELS Study, Subclavian/Axillary cannulation was associated with higher rates of major neurologic complications and seizures. In-hospital mortality was higher after Aortic cannulation, despite no significant differences in incidence of neurological cause of death in these patients. These results encourage vigilance for neurologic complications and neuromonitoring use in patients on ECLS, especially with Subclavian/Axillary cannulation.
- MeSH
- Aorta * MeSH
- Femoral Artery * MeSH
- Subclavian Artery MeSH
- Adult MeSH
- Cardiac Surgical Procedures adverse effects methods MeSH
- Catheterization methods adverse effects statistics & numerical data MeSH
- Middle Aged MeSH
- Humans MeSH
- Extracorporeal Membrane Oxygenation * methods adverse effects statistics & numerical data MeSH
- Hospital Mortality trends MeSH
- Nervous System Diseases etiology epidemiology MeSH
- Catheterization, Peripheral methods adverse effects statistics & numerical data MeSH
- Postoperative Complications epidemiology etiology MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O2) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s-1 and 15 cm·s-1. In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation.NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.
- MeSH
- Hippocampus * metabolism MeSH
- Hypoxia metabolism physiopathology MeSH
- rho-Associated Kinases * metabolism genetics MeSH
- Rats MeSH
- Spinal Cord metabolism physiology MeSH
- Cerebral Cortex metabolism physiology MeSH
- Neuronal Plasticity physiology MeSH
- Rats, Wistar * MeSH
- rho GTP-Binding Proteins MeSH
- rhoA GTP-Binding Protein metabolism MeSH
- Signal Transduction * physiology MeSH
- High-Intensity Interval Training * MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Cerebral air embolism (CAE) is an uncommon medical emergency with a potentially fatal course. We have retrospectively analyzed a set of patients treated with CAE at our comprehensive stroke center and a hyperbaric medicine center. An overview of the pathophysiology, causes, diagnosis, and treatment of CAE is provided. RESULTS: We retrospectively identified 11 patients with cerebral venous and arterial air emboli that highlight the diversity in etiologies, manifestations, and disease courses encountered clinically. Acute-onset stroke syndrome and a progressive impairment of consciousness were the two most common presentations in four patients each (36%). Two patients (18%) suffered from an acute-onset coma, and one (9%) was asymptomatic. Four patients (36%) were treated with hyperbaric oxygen therapy (HBTO), high-flow oxygen therapy without HBOT was started in two patients (18%), two patients (18%) were in critical care at the time of diagnosis and three (27%) received no additional treatment. CAE was fatal in five cases (46%), caused severe disability in two (18%), mild disability in three (27%), and a single patient had no lasting deficit (9%). CONCLUSION: Cerebral air embolism is a dangerous condition that necessitates high clinical vigilance. Due to its diverse presentation, the diagnosis can be missed or delayed in critically ill patients and result in long-lasting or fatal neurological complications. Preventative measures and a proper diagnostic and treatment approach reduce CAE's incidence and impact.
- Publication type
- Journal Article MeSH
BACKGROUND: Limited evidence exists for prognostic performance of biomarkers in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with extracorporeal CPR (ECPR). We hypothesized that (1) the time course and (2) prognostic performance of biomarkers might differ between CPR and ECPR in a sub-analysis of Prague-OHCA study. METHODS: Patients received either CPR (n = 164) or ECPR (n = 92). The primary outcome was favorable neurologic survival at 180 days [cerebral performance category (CPC) 1-2]. Secondary outcomes included biomarkers of neurologic injury, inflammation and hemocoagulation. RESULTS: Favorable neurologic outcome was not different between groups: CPR 29.3% vs. ECPR 21.7%; p = 0.191. Biomarkers exhibited similar trajectories in both groups, with better values in patients with CPC 1-2. Procalcitonin (PCT) was higher in ECPR group at 24-72 h (all p < 0.01). Neuron-specific enolase (NSE), C-reactive protein and neutrophil-to-lymphocyte ratio did not differ between groups. Platelets, D-dimers and fibrinogen were lower in ECPR vs. CPR groups at 24-72 h (all p < 0.001). ROC analysis (24-48-72 h) showed the best performance of NSE in both CPR and ECPR groups (AUC 0.89 vs. 0.78; 0.9 vs. 0.9; 0.91 vs. 0.9). PCT showed good performance specifically in ECPR (0.72 vs. 0.84; 0.73 vs. 0.87; 0.73 vs. 0.86). Optimal cutoff points of NSE and PCT were higher in ECPR vs. CPR. CONCLUSIONS: Biomarkers exhibited similar trajectories although absolute values tended to be higher in ECPR. NSE had superior performance in both groups. PCT showed a good performance specifically in ECPR. Additional biomarkers may have modest incremental value. Prognostication algorithms should reflect the resuscitation method.
- MeSH
- Biomarkers * blood MeSH
- Phosphopyruvate Hydratase blood MeSH
- Cardiopulmonary Resuscitation * methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Extracorporeal Membrane Oxygenation * methods MeSH
- Prognosis MeSH
- Procalcitonin blood MeSH
- Aged MeSH
- Out-of-Hospital Cardiac Arrest * therapy blood mortality MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
