Cerebral Hypoperfusion Research Articles

Connecting the dots: A narrative review of the relationship between heart failure and cognitive impairment.

Large clinical data underscore that heart failure is independently associated to an increased risk of negative cognitive outcome and dementia. Emerging evidence suggests that cerebral hypoperfusion, stemming from reduced cardiac output and vascular pathology, may contribute to the largely overlapping vascular dementia and Alzheimer's disease. Despite these insights, cognitive outcomes remain largely overlooked in heart failure management. This narrative review outlines the prevalence and risk of cognitive impairment in heart failure patients, exploring potential shared pathophysiological mechanisms and examining the impact of heart failure therapy on cognitive deficits. Additionally, it discusses clinical implications and suggests future treatment approaches targeting therapeutic outcomes. Cognitive impairment is prevalent among individuals with heart failure, with reported rates varying widely depending on assessment methods. Shared pathological pathways and risk factors, including atrial fibrillation (AF), hypertension, obesity and type 2 diabetes mellitus, suggest a causal link. Mechanisms such as poor perfusion, microembolic events, ischaemic syndromes and cerebral inflammation contribute to this relationship. Moreover, heart failure itself may exacerbate cognitive dysfunction. This emerging understanding posits that vascular dementia and Alzheimer's disease may represent a pathophysiological continuum, driven by both the accumulation of misfolded proteins and cerebrovascular pathology due to cardiovascular dysfunction. Understanding these links is crucial for developing effective treatment strategies. The complex interplay between heart failure and cognitive impairment underscores the necessity for a holistic patient care approach. Both conditions share analogous disease processes, influencing self-management and independence in patients. Prioritizing brain health in heart failure management is essential to enhance patient prognosis and general well-being.

Hyperbaric Oxygen Improves Cognitive Impairment Induced by Hypoxia via Upregulating the Expression of Oleic Acid and MBOAT2 of Mice

Cognitive impairment (CI) causes severe impairment of brain function and quality of life of patients, which brings a great burden to society. Cerebral hypoxia is an important factor in the pathogenesis of CI. Hyperbaric oxygen (HBO) therapy may mitigate hypoxia-induced CI, but its efficacy and mechanisms are not fully understood. In this study, a mice model of CI induced by hypoxia environment was established, then behavioral tests, pathological examination, metabolomic and lipidomic analyses, and molecular biology were used to assess the impact of HBO on hypoxia-induced CI. HBO was found to alleviate CI and pathological damage of hypoxia mice. Metabolomic, lipidomic, and molecular biology analyses showed that HBO increased the levels of oleic acid (OA) and membrane-bound O-acyltransferase 2 (MBOAT2), thereby altering the composition of membrane phospholipids (PLs) and reducing hypoxia-induced neuronal ferroptosis (FPT) to interfere with cognitive function in mice. In vitro experiments confirmed that OA and MBOAT2 led to membrane PL remodeling in a mutually dependent manner, affecting cell resistance to hypoxia-FPT. The results emphasized the combined effect value of OA and MBOAT2 in HBO for hypoxia-induced CI, and provided a novel perspective for the treatment of CI by HBO.

Prognostic influence of the neurological complications in patients supported with venoarterial extracorporeal membrane oxygenation

Abstract Background Neurologic injuries including ischemic or hemorrhagic stroke and hypoxic-ischemic encephalopathy are common in patients supported with venoarterial extracorporeal membrane oxygenation (VA-ECMO). Purpose Our objective was to analyze the prognostic influence of neurological injuries on in-hospital survival. Methods Retrospective analysis of consecutive VA-ECMO cases in a referal center. We studied the neurological diagnoses and the results of complementary tests (brain computed tomography –CT- and electroencephalogram –EEG-) and their influence on in-hospital evolution. Results 238 VA-ECMO were implanted between oct 2013-jan 2024. Baseline, admission and evolution characteristics are collected in the table. 58.4% of patients had suffered cardiac arrest (prior to VA-ECMO implantation, and extracorporeal cardiopulmonary resuscitation was performed in 28.6% of cases. 6 (2.5%) suffered intracranial hemorrhage, 13 (5.5%) ischemic stroke and 40 (16.8%) some degree of hypoxic-ischemic encephalopathy. In-hospital survival was 32.4% (n=77). In 17.2% of the cases neurological damage influenced death (adequacy of therapeutic effort or non-escalation of therapies) and in 14.7% of cases death was directly due to neurological cause (table). Survival was lower in patients with ischemic (stroke survival 23.1% vs no stroke 33.2%, p=0.555) or hemorrhagic stroke (16.7% vs 33%, p=0.667), although without statistically significant differences. The presence of hypoxic brain damage was related to lower hospital survival (survival in patients with encephalopathy 15% vs. without 36.8%, p=0.009). Best EEG pattern registered was related to survival: I survival 33.3% and II 12.5% (good prognosis), III 25% (uncertain prognosis), IV 16.7% and V 0% (poor prognosis), p=0.048. The presence of status epilepticus showed a non-statistically significant trend towards lower survival (survival status 0% vs no estatus 25%, p=0.082). VA-ECMO preimplantation cardiac arrest was associated with the occurrence of encephalopathy (encephalopathy 84% vs. not 40%, p=0.049). The duration of cardiac arrest and lactate before VA-ECMO implantation were significantly higher as the EEG pattern was worse (figure). Conclusions Neurological damage is relevant in patients under VA-ECMO support, being a determining factor in death in up to 17.2% of patients. Hypoxic-ischemic encephalopathy was associated with lower survival, with the EEG pattern associated with previous cardiac arrest, its duration and lactate.Table.Baseline, admission and follow-upFigure.Cardiac arrest, lactate and EEG

Clinical Characteristics and Outcomes of SARS-CoV-2 Infection in Neonates with Persistent Pulmonary Hypertension of the Newborn (PPHN): A Systematic Review

PPHN is a common cause of neonatal respiratory failure and is still a serious condition that is associated with high mortality. Objectives: To analyze the clinical characteristics and outcomes of SARS-CoV-2 infection in neonates with PPHN to identify neonatal cases at risk to develop severe illness. Methods: For this systematic review, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched Medline, Embase, CINAHL, and PubMed for studies on the development of COVID-19 in neonates with PPHN, published from 1 December 2019 to 29 February 2024, with an English language restriction. Results: Of the 2406 papers that were identified, 21 articles were included in the systematic review. Studies involving thirty-six neonates with PPHN and infected with SARS-CoV-2 were analyzed (twenty-nine survived, six died, and one is still hospitalized). The main causes of PPHN in neonates who had COVID-19 were neonatal respiratory distress syndrome (NRDS) (41.7%), meconium-stained amniotic fluid (MSAF) (16.7%), preterm premature rupture of membranes (PPROM) (11.1%), hypoxic ischemic encephalopathy (HIE) (5.5%), pneumonia (5.5%), and idiopathic (2.8%). Most of those neonates were male (33.3%), belonged to Indian ethnicity (50%), and were delivered via caesarean section (44.4%). COVID-19 in cases with PPHN commonly occurred in neonates born with a pregnancy range from 32 to <37 weeks (moderate to late preterm) (36.1%). The maternal severity of COVID-19 was reported to be severe in three cases only (8.3%); however, SARS-CoV-2 infection in neonates with PPHN was either severe (44.4%) or critical (22.2%). Most of these neonates experienced acute respiratory distress syndrome (ARDS) (58.3%). Early and late multisystem inflammatory syndrome in neonates (MIS-N) were reported in 50% and 11.1%, respectively. A high proportion of neonates were admitted to the intensive care unit (ICU) (58.3%) or needed mechanical ventilation (MV) (47.2%). Neonates with concurrent PPHN and SARS-CoV-2 infection who died had worse severity of COVID-19 [i.e., severity of COVID-19 was critical in 10% (neonates with PPHN who survived group) vs. 83.3% (neonates with PPHN who died group); p = 0.026]. Neonates with PPHN and COVID-19 had a higher relative risk of death if they received more antibiotics (RR 4.14, 95% CI 0.64–6.88) and if their COVID-19 was defined as critical (RR 2.84, 95% CI 0.86–9.39). Male neonates with PPHN and COVID-19 (RR 2.60, 95% CI 0.30–1.17) and those requiring prolonged invasive positive pressure ventilation (RR 2.22, 95% CI 0.64–7.73) also showed an increased relative risk for death. Conclusions: COVID-19 in neonates with PPHN is challenging and may be associated with increased mortality, severity, ICU admission, ARDS, MIS-N, and MV usage. The results should be interpreted with caution owing to the small number of studies and substantial heterogeneity and indicate a need for future research in this area. Due to its benefits, testing for SARS-CoV-2 should be encouraged for newborns with symptoms consistent with COVID-19, especially in neonates with a history of SARS-CoV-2 exposure. Effective protection measures should be implemented during delivery and post-delivery care as necessary.

Increased miRNA-related inflammation markers and pro-inflammatory circulating cell profile in patients with poor neurological outcome after out-of-hospital cardiac arrest

Abstract Background Out-of-Hospital Cardiac Arrest (OHCA) supposes a main cause of disability and mortality worldwide. Between patients suffering OHCA, only a 10-20% can be successfully resuscitated and, between them, a 50% suffers of neurological sequelae. Mechanisms underlying brain damage seems to be strongly related with neuroinflammation, mediated by classical (PCR, NLR) and novel (miRNAs) agents at play. Even there are studies suggesting the relevance of miRNA-mediated inflammatory response in ECA, no consistent conclusions about its role in ECA outcomes have been obtained. Purpose The aim of the present investigation is to study the temporal patterns of classical (PCR, NLR) and novel (miRNAs) inflammation markers during hospitalization of ECA patients and to correlate them with neurological outcome. Methods Consecutive OHCA patients were prospectively recruited at the Acute Cardiac Care Unit (ACCU) of the hospital Clinic of Barcelona from March 2019 to December 2023. Serum samples were obtained at 0, 24 and 72 hours after hospital admission. Patients were grouped according to their neurological outcome, measured by Cerebral Performance Category (CPC), at hospital discharge. Classical inflammation markers (PCR and NLR) were measured and in silico pre-targeted serum circulating-miRNAs were analysed by qPCR. Results A total of 120 patients (60 ± 13 years, 20% female) were included for the analysis. At hospital discharge, 55 (45%) patients survived with good NO (GNO; CPC 1-2) and 65 (55%) patients presented a poor NO (PNO; CPC 3-5). Classical inflammation markers such as PCR and NLR were significant higher in PNO than in GNO Group (P-value = 0.0042 and p-ANOVA = 0.0444, respectively) (Figure 1A). 11 inflammation-related miRNAs with strong correlation with OHCA-related conditions such as cardiovascular and coronary artery disease, hypoxic encephalopathy and neuro-inflammation were pre-targeted by in silico analysis. Five of the pre-targetedmiRNAs (miR-21-5p, miR-23a-3p, miR-146-5p, miR-155-5p and miR-181a-5p) presented significant differences between GNO and PNO groups (p-ANOVA = 0.0001, 0.0027, 0.0001, 0.0023 and 0.0002 respectively) in at least one time point, with an reduced expression in all cases in the PNO respect the GNO group (Figure 1B). Conclusions Patients with PNO after OHCA presents a downregulation of inflammation-regulatory miRNAs that leads an increase of clinical inflammation-related mediators such as PCR and NLR, with potential neuro-inflammatory consequences.

Hypoxia-inducible factor-1 as targets for neuroprotection : from ferroptosis to Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor paralysis, tremor,and cognitive impairment. Risk factors such as brain hypoxia caused by aging and abnormal expression of HIF-1α areconsidered to be key to the development of PD, including α-synuclein accumulation and ferroptosis. However, therelationship between HIF-1α signaling and ferroptosis in PD has not been elucidated. The stable expression of HIF-1αinhibits the pathological development of PD. Aging aggravates PD pathology by promoting α-synuclein accumulationand oxidative stress. The literature on lipid peroxidation, oxidative stress, iron metabolism and other key factors in Parkinson'sdisease in recent years was reviewed through a variety of literature search channels, such as PubMed and Elsevier. HIF-1α mediated ferroptosis through oxidative stress and GPX4-GSH system. HIF-1α mediates ferroptosisthrough Keap1-Nrf2-ARE, Grx3 and Grx4. HIF-1α mediates ferroptosis through iron metabolism. This article reviews the oxygen-dependent regulatory mechanism of HIF-1α and its role in cerebralhypoxia homeostasis. Studies in the past decade have shown that Hif-1α mediated ferroptosis is important in PD.HIF-1α has a dual role, depending on the degree of cellular hypoxia and the environment. The equilibrium complexityneeds to be explained, and the role of ferroptosis needs to be investigated. The literature shows that the stabilizationof HIF-1α with PHD inhibitors and the combination of antioxidants and iron chelators are potential therapeuticdirections. In the future, the optimal use time and dose of inhibitors should be studied to improve the efficacy.

The majority of 30-days survivors return to work one-year after in-hospital cardiac arrest

Abstract Background Surviving in-hospital cardiac arrest poses a significant risk of anoxic brain damage, which can impede survivors’ ability to return to work. Purpose This study aimed to examine return to work among in-hospital cardiac arrest survivors. Methods In this cohort study we included all 30-day survivors of working age (18-64 years), who experienced an in-hospital cardiac arrest between January 1st, 2013, and December 31st, 2018. Data was obtained from the national Danish in-hospital cardiac arrest registry (DANARREST) and employment status was retrieved from a registry from the Danish National Labor Market Authorities. We used a previously validated definition of "working" as any individual who was not on any social benefits, except state education fund grants, maternity leave pays, or leave-of-absence. Only patients working four weeks prior to the event were included in the study. Kaplan-Meier survival analysis was applied to estimate the probability of returning to work. Results Among 7,254 in-hospital cardiac arrest patients in Denmark from 2013-2018, 1,781 were of working-age, with 734 surviving at least 30 days. A total of 348 patients, who were working four weeks before their event, formed the final study population (Figure 1). Median age was 54 (Interquartile range (IQR) 46-59) and 70.4% were male. The cumulative incidence for return to work was 67.0% (95% CI: 62.0%-71.9%) with 4.6% (95% CI: 2.4%-6.8%) dying by one-year post-arrest as a competing risk (Figure 2). Age and sex distribution were comparable between survivors returning to work, those who did return to work, and those who died. A higher proportion of survivors returning to work had a Carlson’s Comorbidity Index score of 1 (70.8%) compared to survivors without work (58.1%) and those who died (33.3%). Additionally, an initial shockable rhythm was more frequent among survivors returning to work (49.8%) compared to survivors who did not return to work (45.2%), and those who died (9.1%). Conclusion We found that 67% of 30-day survivors of in-hospital cardiac arrest returned to work one year after their event. While survivors retuning to work shared comparable age and sex distributions with survivors who did not return to work and non-survivors, factors such as a lower Carlson’s Comorbidity Index score and a higher proportion with an initial shockable rhythm were distinguishing characteristics for those who returned to work.FlowchartCumulative incidence curves

Effect of nelonemdaz for patients with out-of-hospital cardiac arrest: the AWAKE phase II randomised clinical trial

Abstract Background Hypoxic brain injury is a major hurdle that limits the survival of out-of-hospital cardiac arrest (OHCA). Nelonemdaz is a dual-target neuroprotectant, serving as a moderate NR2B-selective N-methyl-D-aspartate (NMDA) receptor antagonist while also exhibiting potent free radical scavenger properties. This dual neuroprotective action of nelonemdaz has the potential to reduce hypoxic brain injury in OHCA. We investigated the efficacy and safety of nelonemdaz for patients with OHCA. Methods AWAKE trial was a double-blind, placebo-controlled, randomised, multicentre phase II trial at 5 sites in South Korea. OHCA patients undergoing targeted temperature management were randomly assigned to high-dose (5250 mg), low-dose (3250 mg), and placebo groups at a 1:1:1 ratio. The primary outcome was the blood level of neuron-specific enolase (NSE) after 4th administration of drug. Secondary outcomes comprised blood biomarkers including neuron specific enolase (NSE) and S100beta, brain magnetic resonance imaging (MRI), and Cerebral Performance Category (CPC) and Modified Rankin Scale (mRS) up to day 90. Safety is assessed by serious adverse event. Findings: A total of 105 patients were enrolled between November 18, 2018 to February 23, 2023. Patients with a median age of 61 years and 82% male were assigned to the high-dose (N=37), low-dose (N=35), and placebo (N=33) groups. Primary outcome was evaluated in 93 patients. There was no difference of neuron specific enolase (NSE, ng/mL), which served as the primary endpoint, between high-dose (median and interquartile range; 23·7, 15·0–69·9) and placebo (17·5, 13·6–113·0) groups and also between low-dose (26·6, 16·2–83·4) versus placebo groups (all p>0·05). Among secondary outcomes, fractional anisotropy of brain MRI was significantly higher in high-dose group compared to placebo group (0·465, 0·449–0·485 versus 0·441, 0·431–0·464; p=0·028), and was not different between low-dose (0·462, 0·439–0·480) and placebo groups (p>0·05). At day 90, the common odds ratio (95% confidence interval) indicating a favourable shift in the modified Rankin Scale was 1·25 (0·48–3·24) and 1·22 (0·47–3·20) in the high-dose and low-dose groups respectively, compared to placebo group (all p>0·05). No serious adverse events were reported. Interpretation: Nelonemdaz did not reduced blood NSE level of OHCA patients. However, patients treated with high-dose nelonemdaz showed better fractional anisotropy that suggests reduced cerebral white matter damage. Patients treated with nelonemdaz also showed a favourable tendency of neurological recovery at day 90 without significant adverse effects. These results justify the initiation of a large-scale phase III trial.Neurological function up to day 90

Long-term outcomes of heart re-transplantation from HCV-viremic donors based on UNOS registry

Abstract Background The use of hepatitis C virus (HCV) viremic donors increased the heart donor pool, and reduced waitlist time and mortality among first-time single-organ heart transplant (HT) candidates without compromising their post-transplant survival. The outcomes of heart re-transplantation (re-HT) with the use of HCV-viremic donor grafts have not been investigated. Methods Using the United Network of Organ Sharing (UNOS) Registry we analyzed all adult patients who underwent single-organ heart re-HT in the United States between January 1, 2016, and December 31, 2022. HCV-viremic donors were defined by a positive nucleic acid amplification test (NAT+). Graft survival rates between HCV-viremic and HCV-non-viremic donor graft recipients were compared using a log rank test. Results During the study period, of 18,259 HTs performed, 427 (2.3%) constituted single-organ heart re-transplantations. Recipients of NAT+ grafts (n=19) compared to NAT- grafts (n=408) were more often male (84.2% vs 61.3%, p=0.04). Otherwise, there were no significant differences between the two groups in age, ethnicity, BMI, blood type, history of diabetes rates or stroke, creatinine or bilirubin levels, reason for re-HT, hemodynamics, use of mechanical circulatory support, and waitlist time. Ischemic time, frequency of female donors, HLA, ABO, CMV mismatch rates, and calculated panel reactive antibodies levels were comparable across the two groups. There were no significant differences in demographics or comorbidities rates between HCV-viremic and HCV-non-viremic donors apart from the cause of death. Among the donors of HCV-viremic grafts brain anoxia was reported more often (89.5%) than among HCV-non-viremic donors (40%), p <0.01. Rates of acute rejection treated in the first year after re-HT were comparable across the two groups. Over a mean follow-up of 3.0±2.1 and 3.3±1.8 years after re-HT from NAT- and NAT+ organ donors, respectively, graft survival rate at 1 year was 82% vs. 95% (p=0.3) and at 3 years 79% vs. 89%, respectively (p=0.6) (Figure). Conclusion Graft survival rates at 1 and 3 years post-heart re-HT in adult recipients of HCV-viremic donor grafts were comparable to those of recipients of HCV-non-viremic donor grafts. The current study provides compelling preliminary evidence that HCV-viremic donors constitute a viable donor pool for patients in need of heart re-transplantation.

Exploring the role of HIF-1α on pathogenesis in Alzheimer's disease and potential therapeutic approaches.

Hypoxia-inducible factor 1α (HIF-1α) is a crucial transcription factor that regulates cellular responses to low oxygen levels (hypoxia). In Alzheimer's disease (AD), emerging evidence suggests a significant involvement of HIF-1α in disease pathogenesis. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to neuronal dysfunction and cognitive decline. HIF-1α is implicated in AD through its multifaceted roles in various cellular processes. Firstly, in response to hypoxia, HIF-1α promotes the expression of genes involved in angiogenesis, which is crucial for maintaining cerebral blood flow and oxygen delivery to the brain. However, in the context of AD, dysregulated HIF-1α activation may exacerbate cerebral hypoperfusion, contributing to neuronal damage. Moreover, HIF-1α is implicated in the regulation of Aβ metabolism. It can influence the production and clearance of Aβ peptides, potentially modulating their accumulation and toxicity in the brain. Additionally, HIF-1α activation has been linked to neuroinflammation, a key feature of AD pathology. It can promote the expression of pro-inflammatory cytokines and exacerbate neuronal damage. Furthermore, HIF-1α may play a role in synaptic plasticity and neuronal survival, which are impaired in AD. Dysregulated HIF-1α signaling could disrupt these processes, contributing to cognitive decline and neurodegeneration. Overall, the involvement of HIF-1α in various aspects of AD pathophysiology highlights its potential as a therapeutic target. Modulating HIF-1α activity could offer novel strategies for mitigating neurodegeneration and preserving cognitive function in AD patients. However, further research is needed to elucidate the precise mechanisms underlying HIF-1α dysregulation in AD and to develop targeted interventions.

A systematic catalog of studies on fetal heart rate pattern and neonatal outcome variables.

To study the methodology and results of studies assessing the relationship between fetal heart rate and specified neonatal outcomes including, heart rate, infection, necrotizing enterocolitis, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, and seizure. Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and CINAHL were searched from inception to October 5, 2023. Forty-two studies were included, encompassing 57,232 cases that underwent fetal monitoring and were evaluated for neonatal outcome. Heterogeneity was observed in the timing and duration of fetal heart rate assessment, classification guidelines used, number of assessors, and definition and timing of neonatal outcome assessment. Nonreassuring fetal heart rate was linked to lower neonatal heart rate variability. A significant increase in abnormal fetal heart rate patterns were reported in neonates with hypoxic-ischemic encephalopathy, but the predictive ability was found to be limited. Conflicting results were reported regarding sepsis, seizure and intraventricular hemorrhage. No association was found between necrotizing enterocolitis rate and fetal heart rate. There is great heterogeneity in the methodology used in studies evaluating the association between fetal heart rate and aforementioned neonatal outcomes. Hypoxic-ischemic encephalopathy was associated with increased abnormal fetal heart rate patterns, although the predictive ability was low. Further research on developing and evaluating an automated early warning system that integrates computerized cardiotocography with a perinatal health parameter database to provide objective alerts for patients at-risk is recommended.

Xenon and Argon as Neuroprotective Treatments for Perinatal Hypoxic-Ischemic Brain Injury: A Preclinical Systematic Review and Meta-Analysis.

Xenon and argon are currently being evaluated as potential neuroprotective treatments for acquired brain injuries. Xenon has been evaluated clinically as a treatment for brain ischemia with equivocal results in small trials, but argon has not yet undergone clinical evaluation. Several preclinical studies have investigated xenon or argon as treatments in animal models of perinatal hypoxic-ischemic encephalopathy (HIE). A systematic review of MEDLINE and Embase databases was performed. After screening of titles, abstracts, and full text, data were extracted from included studies. A pairwise meta-analysis of neuroprotective efficacy was performed using a random effects model. Heterogeneity was investigated using subgroup analysis, funnel plot asymmetry, and Egger's regression. The protocol was prospectively registered on PROSPERO (CRD42022301986). A total of 21 studies met the inclusion criteria. The data extracted included measurements from 1591 animals, involving models of HIE in mice, rats, and pigs. The meta-analysis found that both xenon and argon had significant (P < .0001) neuroprotective efficacies. The summary estimate for xenon was 39.7% (95% confidence interval [CI], 28.3%-51.1%) and for argon it was 70.3% (95% CI, 59.0%-81.7%). The summary effect for argon was significantly (P < .001) greater than that of xenon. Our results provide evidence supporting further investigation of xenon and argon as neuroprotective treatments for HIE.

Gentamicin Pharmacokinetics in Neonates Undergoing Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy.

The purpose of this study was to review the pharmacokinetic profile of gentamicin among neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) treatment. This was a retrospective study of neonates with HIE undergoing TH in the neonatal intensive care unit who received gentamicin between 2009 and 2014. Demographic information, diagnoses, laboratory test results, and medication administration and monitoring information were collected, and data were analyzed using SciPy. A total of 57 neonates were analyzed. The median birth weight was 3.25 kg (interquartile range [IQR] 2.8-3.68), and median gestational age was 39 weeks (IQR 38-40). An elevated gentamicin trough level (defined as > 2 mg/L) was observed in 61% (35/57) of neonates. Half of the neonates (49%) had multiple gentamicin trough levels obtained, and 4% of the neonates were switched to an alternate agent. There was a significant difference in the number of dosing interval changes in neonates with elevated gentamicin trough levels compared with those with therapeutic gentamicin trough levels (P < 0.001). Of the neonates with elevated gentamicin trough levels, 14% (5/35) failed their hearing screen (P = 0.389). Neonates with HIE undergoing TH may have an altered pharmacokinetic profile, requiring multiple blood draws so medication levels can be monitored and doses adjusted.Traditional gentamicin dosing regimens may not be ideal for this patient population, and further guidance is required for alternative treatment regimens.

Running for two (or three!): The journey of an ultramarathoner across two pregnancies.

There is a lack of evidence regarding the safety of long-duration and vigorous intensity physical activity during pregnancy, such as that required during an ultramarathon. This case study is the first to examine the training, performance, health, and delivery outcomes for an ultramarathoner across two successive pregnancies (one twin and one singleton) that were delivered when the athlete was 41 and 43 years, respectively.. During her twin pregnancy, she ran an average of 91.72 ± 23.17 kilometers across 9.06 ± 2.38 hours per week. Both twins were normal for gestational age and delivered at 37 weeks. Twin B experienced mild hypoxic-ischemic encephalopathy, but made a full recovery following treatment. Twin pregnancy increases risk of this complication and there is no evidence to suggest that it is associated with vigorous intensity endurance activity. During her singleton pregnancy, the participant's distance and pace increased, running on average 157.80 ± 14.69 kilometers across 14.08 ± 1.60 hours per week. She also competed in 5 races including 3 ultramarathons and ranked well, with no adverse events during or following each of the races. She delivered prematurely (36 weeks and 6 days), but her baby was normal for gestational age.

Cardiac dysfunction associated with lacosamide in a premature infant with Hypoxic Ischemic Encephalopathy: A case report.

Lacosamide [Vimpat® Harris FRC Corporation. © 2022 UCB, Inc. Smyrna, GA 30080] is an antiseizure medication which acts through blockage of voltage-gated neuronal sodium channels. Its recent implementation in the neonatal population has been extrapolated from adult and pediatric data suggesting a favorable safety profile. (1) Of note, preterm infants have unique developmental characteristics that may predispose them to increased risk of adverse reactions. We present a case of a preterm neonate who developed left ventricular (LV) dysfunction coinciding with the initiation of lacosamide.

Exploring the Relationship Between Hypertension and Cerebral Microvascular Disease

Background/Objectives: Hypertension exerts negative effects on the vasculature representing a key risk factor for cardiovascular disorders, cerebral and Cerebral Small Vessel Disease (CSVD). Methods: An extensive research in the literature was implemented in order to elucidate the role of hypertension in the pathogenesis of CSVD. Results: Hypertension-mediated vascular dysfunction and chronic cerebral hypoperfusion are closely linked to CSVD. CSVD encompasses a wide range of lesions depicted on brain Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scans. The presenting symptoms and clinical course are highly variable, as a significant proportion of patients remain asymptomatic. Nevertheless, CSVD is associated with an increased risk of stroke, dementia and mobility disorders. Various randomised controlled trials have been implemented trying to shed light on the effect of vascular risk-modifying agents and lifestyle interventions on the prevention and treatment of small vessel disease. Conclusions: Hypertension has a pivotal role in the pathogenesis of CSVD. However, further research is required for a better understanding of the relationship between blood pressure levels and CSVD progression.

Web-based training and certification of clinical staff during the randomised clinical trial SafeBoosC-III

BackgroundSafeBoosC-III is a pragmatic, multinational clinical trial evaluating cerebral oximetry-guided treatment for extremely preterm infants. In total, 1601 infants were randomised across 70 sites in Asia, Europe, and USA. To enhance data quality and patient care, a web-based training program was implemented for staff. We now report on the processes.MethodsAll training modules consisted of initial learning material followed by a case-based quiz, with elaborate responses to correct as well as to wrong answers. Modules covered trial introduction, cerebral oximetry monitoring, treatment guidelines, cerebral ultrasound, and Good Clinical Practice. The introduction module was accessible in eight languages on an online platform, while language versions varied for other modules, due to different needs. Certification was earned upon module completion, relevant to the staff category. The training was not mandatory, but for motivational purposes, principal investigators continuously received local certification rate reports.ResultsA total of 926 out of 2347 staff (39%) obtained certification. Amongst 295 staff who completed the evaluation, 83% rated the program as overall good and 94% found it relevant to clinical practice. Sites exhibited varying certification rates, with 10 at 0%, 43 between 0.1 and 79.9%, and 17 exceeding 80%. There was no correlation between the rate of certification in individual sites and how often the clinical management was changed due to cerebral hypoxia nor a correlation to site-specific estimates of the intervention effect.ConclusionDespite language barriers and a low budget, our web-based training and certification program proved feasible. Only a minority of sites reached 80% certification of staff and an impact on the trial could not be detected.Trial registrationThe SafeBoosC-III trial is registered at ClinicalTrials.gov NCT03770741. The first participant was randomised in June 2019 and recruitment was completed in December 2021.

Neurodevelopmental outcome in children between one and five years after persistent pulmonary hypertension of term and near-term newborns.

Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition that affects 1-2 per 1,000 newborns. Scientific data report the existence of neurological developmental abnormalities between 10 and 30%, but the description of these disorders linked with this situation of cerebral hypoxia and haemodynamic failure remains poorly documented. The main goal of this study was to describe the prevalence of neuro-psychomotor developmental disorders in children aged between one and five years old who have been hospitalised at birth in a neonatal intensive care unit for the management of PPHN. All of the newborns ≥34 weeks of gestational age (WGA) with PPHN, treated with inhaled nitric oxide in our neonatal intensive care unit between January 2015 and December 2019 were retrospectively enrolled. An ASQ-3 standardised questionnaire, adapted to the appropriate age (12, 24, 36, 48 and 60 months) was performed by the parents. Fifty-five children (81% of answers) with a median age of 36 months (11-68), whose real age was close to the one of the questionnaire (12, 24, 36, 48 and 60 months), have been included in this study. There was 47% of pathological score [borderline: less than 1 standard deviation (SD) or suspect: less than 2SD] in at least one of the five studied domains, mainly in communication (25%) and individual and social skills (22%), despite a high overall score of 250 [220; 285] out of 300 that improved with age. This study showed a significant prevalence of neuro-psychomotor developmental disorders which justifies making more accessible a prolonged and adapted follow-up for early and multidisciplinary screening and management of these children with PPHN history. Larger cohorts are needed to better explore long term outcome of these vulnerable term neonates.

Fifteen Years of Neonatal Therapeutic Hypothermia: Clinical Trends Show Unchanged Post-Rewarming Outcomes despite Reduction in Hypoxic-Ischemic Encephalopathy Severity

Introduction: Hypoxic-ischemic encephalopathy (HIE) affects 1–2 per 1,000 births and is associated with mortality and long-term neurodevelopmental challenges. At present, therapeutic hypothermia (TH) is the only neuroprotective intervention for these infants. This study examines whether HIE severity, clinical management during TH, and post-rewarming outcomes have changed since its introduction 15 years ago. Methods: Neonatal characteristics, HIE severity, management during TH, and post-rewarming MRI of all infants with HIE undergoing TH between 2008 and 2023 were compared across three five-year epochs. Linear regression was used to estimate annual changes over time. Results: In total, 252 infants underwent TH. Median gestational age (39.5 weeks), birth weight (3,376 g), and time to start TH (4.25 h) remained stable over time. Apgar score at 5 min (p = 0.031) and lowest pH <1 h postpartum (p = 0.020) increased over time. Thompson score at 1–3 h decreased across epochs (p = 0.046). There was an increase in percentage with normal-mild aEEG background patterns on admission (p = 0.041) and a decrease in aEEG-confirmed seizures (p < 0.001) and antiseizure medication (p < 0.001). Inotropic support decreased (p = 0.007), and use of invasive mechanical ventilation decreased over the last 5 years. Mortality (28.6%) and post-rewarming composite adverse outcome (i.e., neonatal mortality and/or adverse MRI score) (37.9%) remained unchanged. Number of infants seen at 2-year follow-up increased (p < 0.001). Conclusion: Over the last 15 years, we treated more infants with milder HIE, as indicated by lower Thompson and milder aEEG scores, and the need for invasive cardiorespiratory support declined. However, there were no improvements in composite adverse outcome (mortality and/or adverse MRI score).

Paroxysmal sympathetic hyperactivity syndrome after recurrent stroke: A case report

Paroxysmal sympathetic hyperactivity (PSH) is a state of autonomic dysfunction characterized by symptoms such as tachypnea, tachycardia, hypertension, hyperthermia, sweating, and dystonia. It can occur after traumatic brain injury, hypoxic-ischemic encephalopathy, and diseases such as stroke. Hypoxia, extensive axonal damage, and young age are believed to predispose to the development of PSH. These patients may be diagnosed with pulmonary embolism, septicemia, or epileptic seizures. Delays in diagnosis prolong hospital stay. Here, we present an 81-year-old man who developed PSH after a recurrent stroke and our management.