Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

Free radicals play a role of paramount importance in the development of neonatal brain injury. Depending on the pathophysiological mechanisms underlying free radical overproduction and upon specific neonatal characteristics, such as the GA-dependent maturation of antioxidant defenses and of cerebrovascular autoregulation, different profiles of injury have been identified. The growing evidence on the detrimental effects of free radicals on the brain tissue has led to discover not only potential biomarkers for oxidative damage, but also possible neuroprotective therapeutic approaches targeting oxidative stress. While a more extensive validation of free radical biomarkers is required before considering their use in routine neonatal practice, two important treatments endowed with antioxidant properties, such as therapeutic hypothermia and magnesium sulfate, have become part of the standard of care to reduce the risk of neonatal brain injury, and other promising therapeutic strategies are being tested in clinical trials. The implementation of currently available evidence is crucial to optimize neonatal neuroprotection and to develop individualized diagnostic and therapeutic approaches addressing oxidative brain injury, with the final aim of improving the neurological outcome of this population.

Transient Hypoperfusion to Ischemic/Anoxic Spreading Depolarization is Related to Autoregulatory Failure in the Rat Cerebral Cortex

Background In ischemic stroke, cerebral autoregulation and neurovascular coupling may become impaired. The cerebral blood flow (CBF) response to spreading depolarization (SD) is governed by neurovascular coupling. SDs recur in the ischemic penumbra and reduce neuronal viability by the insufficiency of the CBF response. Autoregulatory failure and SD may coexist in acute brain injury. Here, we set out to explore the interplay between the impairment of cerebrovascular autoregulation, SD occurrence, and the evolution of the SD-coupled CBF response. Methods Incomplete global forebrain ischemia was created by bilateral common carotid artery occlusion in isoflurane-anesthetized rats, which induced ischemic SD (iSD). A subsequent SD was initiated 20–40 min later by transient anoxia SD (aSD), achieved by the withdrawal of oxygen from the anesthetic gas mixture for 4–5 min. SD occurrence was confirmed by the recording of direct current potential together with extracellular K+ concentration by intracortical microelectrodes. Changes in local CBF were acquired with laser Doppler flowmetry. Mean arterial blood pressure (MABP) was continuously measured via a catheter inserted into the left femoral artery. CBF and MABP were used to calculate an index of cerebrovascular autoregulation (rCBFx). In a representative imaging experiment, variation in transmembrane potential was visualized with a voltage-sensitive dye in the exposed parietal cortex, and CBF maps were generated with laser speckle contrast analysis. Results Ischemia induction and anoxia onset gave rise to iSD and aSD, respectively, albeit aSD occurred at a longer latency, and was superimposed on a gradual elevation of K+ concentration. iSD and aSD were accompanied by a transient drop of CBF (down to 11.9 ± 2.9 and 7.4 ± 3.6%, iSD and aSD), but distinctive features set the hypoperfusion transients apart. During iSD, rCBFx indicated intact autoregulation (rCBFx < 0.3). In contrast, aSD was superimposed on autoregulatory failure (rCBFx > 0.3) because CBF followed the decreasing MABP. CBF dropped 15–20 s after iSD, but the onset of hypoperfusion preceded aSD by almost 3 min. Taken together, the CBF response to iSD displayed typical features of spreading ischemia, whereas the transient CBF reduction with aSD appeared to be a passive decrease of CBF following the anoxia-related hypotension, leading to aSD. Conclusions We propose that the dysfunction of cerebrovascular autoregulation that occurs simultaneously with hypotension transients poses a substantial risk of SD occurrence and is not a consequence of SD. Under such circumstances, the evolving SD is not accompanied by any recognizable CBF response, which indicates a severely damaged neurovascular coupling.

Experimental high thoracic spinal cord injury impairs the cardiac and cerebrovascular response to orthostatic challenge in rats

This is the first use of LBNP to interrogate the cardiac and cerebrovascular responses to simulated OH in a preclinical study of SCI. Here, we demonstrate the utility of our simulated OH model and use it to demonstrate that SCI impairs the cardiac response to simulated OH and disrupts dynamic cerebrovascular autoregulation.

Cerebral microbleeds and hemodynamic changes in individuals with cognitive impairment

Background & Objective: Cerebral microbleeds (CMBs) are considered key markers of small vessel pathology linking mechanisms relating to ischemic and amyloid related vascular damage in Alzheimer disease (AD). We aim to investigate the differences of hemodynamic markers between patients with and without CMBs who presented with cognitive decline using transcranial Doppler (TCD) ultrasonography. Methods: We consecutively enrolled patients who were diagnosed with mild cognitive impairment (MCI) and probable AD dementia from May 2011 to December 2012. Using TCD ultrasonography, cerebrovascular reactivity (CVR) was evaluated with hyperventilation (HV) and breath-holding (BH) tests in addition to mean flow velocity (MFV) and pulsatility index (PI) of the middle cerebral artery. The number and location of CMBs were visually analyzed by two independent neurologists. Results: A total of 134 patients (probable AD, n=81; MCI, n=53) were enrolled in this study. Among them, 28 (20.9%) patients had CMBs; 18 (64.3%) lobar CMBs, 7 (25.0%) non-lobar CMBs. Patients with CMBs showed reduced MFV, higher resistance index value, and lower CVR compared with patients without CMBs after adjusting for age, vascular risk factors, and white matter hyperintensity. Multiple regression models showed that PI was dependent on age and presence of CMBs in frontal and parietal areas. CVR was closely associated with WMH severity and presence of CMBs in temporal. Conclusions: Our study showed that patients with CMBs had higher microvascular resistance and decreased cerebrovascular autoregulation compared to those without.

Usefulness of Cerebral Oximetry in TBI by NIRS

Measurement of cerebral oximetry by near-infrared spectroscopy provides continuous and non-invasive information about the oxygen saturation of haemoglobin in the central nervous system. This is especially important in the case of patients with traumatic brain injuries. Monitoring of cerebral oximetry in these patients could allow for the diagnosis of inadequate cerebral oxygenation caused by disturbances in cerebral blood flow. It could enable identification of episodes of hypoxia and cerebral ischemia. Continuous bedside measurement could facilitate the rapid diagnosis of intracranial bleeding or cerebrovascular autoregulation disorders and accelerate the implementation of treatment. However, it should be remembered that the method of monitoring cerebral oximetry by means of near-infrared spectroscopy also has its numerous limitations, resulting mainly from its physical properties. This paper summarizes the usefulness of monitoring cerebral oximetry by near-infrared spectroscopy in patients with traumatic brain injury, taking into account the advantages and the disadvantages of this technique.

817 Robotic Semi-Automated Transcranial Doppler Assessment of Cerebrovascular Autoregulation in Post Concussional Syndrome: Methodological Considerations

Introduction Post-concussive syndrome (PCS) refers to a constellation of physical, cognitive, and emotional symptoms after traumatic brain injury (TBI). Despite its incidence, the underlying mechanisms are unclear. We hypothesised that impaired cerebral autoregulation (CA) is a contributor. Method A prospective, observational study was integrated into outpatient clinics at a tertiary neurosurgical centre. Data points included: demographics, symptoms (Post-Concussion Symptom Scale [PCSS]), neuropsychological assessment (Cambridge Neuropsychological Test Automated-Battery [CANTAB]) and cerebrovascular metrics (Mxa co-efficient and the transient hyperaemic-response ratio [THRR]) - via transcranial Doppler (TCD), plethysmography and bespoke software (ICM+). Results 12 participants were recruited with 2 excluded after unsuccessful cerebrovascular TCD insonation. 10 participants (5 TBI patients, 5 healthy controls) were included in the analysis (median age 26.5, male:female 7:3). Median PCSS scores were 6/126 (TBI subgroup). Median CANTAB percentiles were 78 (healthy controls) and 25 (TBI). Mxa was calculated for 90% and THRR for 50% of participants. Median study time was 127.5 minutes and feedback (n = 6) highlighted the perceived acceptability of the study. Conclusions This pilot study has demonstrated a feasible and reproducible assessment of PCS and CA metrics (non-invasively) in a real-world setting. By scaling this methodology, we hope to test whether CA changes are correlated with symptomatic PCS in patients post-TBI.

Intraoperative impaired cerebrovascular autoregulation and delayed neurocognitive recovery after major oncologic surgery: a secondary analysis of pooled data

Cerebral blood flow is tightly regulated by cerebrovascular autoregulation (CVA), and intraoperative impairment of CVA has been linked with perioperative neurocognitive disorders. We aim to assess whether impairment of CVA during major oncologic surgery is associated with delayed neurocognitive recovery (DNCR) postoperatively. We performed a secondary analysis of prospectively collected data. Patients were included if they had undergone complete pre- and postoperative neuropsychological assessments, continuous intraoperative measurement of CVA, and major oncologic surgery for visceral, urological, or gynecological cancer. Intraoperative CVA was measured using the time-correlation method based on near-infrared-spectroscopy, and DNCR was assessed with a neuropsychological test battery. A decline in cognitive function before hospital discharge compared with a preoperative baseline assessment was defined as DNCR. One hundred ninety-five patients were included in the analysis. The median age of the study population was 65 years (IQR: 60–68); 11 patients (5.6%) were female. Forty-one patients (21.0%) fulfilled the criteria for DNCR in the early postoperative period. We found a significant association between impaired intraoperative CVA and DNCR before hospital discharge (OR = 1.042 [95% CI: 1.005; 1.080], p = 0.028). The type of surgery (radical prostatectomy vs. other major oncologic surgery; OR = 0.269 [95% CI: 0.099; 0.728], p = 0.010) and premedication with midazolam (OR = 3.360 [95% CI: 1.039; 10.870], p = 0.043) were significantly associated with the occurrence of DNCR in the early postoperative period. Intraoperative impairment of CVA is associated with postoperative neurocognitive function early after oncologic surgery. Therefore, intraoperative monitoring of CVA may be a target for neuroprotective interventions. The initial studies were retrospectively registered with primary clinical trial registries recognized by the World Health Organization (ClinicalTrials.gov Identifiers: DRKS00010014, 21.03.2016 and NCT04101006, 24.07.2019).

Cerebrovascular autoregulation and arterial carbon dioxide in patients with acute respiratory distress syndrome: a prospective observational cohort study

Background Early hypercapnia is common in patients with acute respiratory distress syndrome (ARDS) and is associated with increased mortality. Fluctuations of carbon dioxide have been associated with adverse neurological outcome in patients with severe respiratory failure requiring extracorporeal organ support. The aim of this study was to investigate whether early hypercapnia is associated with impaired cerebrovascular autoregulation during the acute phase of ARDS. Methods Between December 2018 and November 2019, patients who fulfilled the Berlin criteria for ARDS, were enrolled. Patients with a history of central nervous system disorders, cerebrovascular disease, chronic hypercapnia, or a life expectancy of less than 24 h were excluded from study participation. During the acute phase of ARDS, cerebrovascular autoregulation was measured over two time periods for at least 60 min. Based on the values of mean arterial blood pressure and near-infrared spectroscopy, a cerebral autoregulation index (COx) was calculated. The time with impaired cerebral autoregulation was calculated for each measurement and was compared between patients with and without early hypercapnia [defined as an arterial partial pressure of carbon dioxide (PaCO2) ≥ 50 mmHg with a corresponding arterial pH < 7.35 within the first 24 h of ARDS diagnosis]. Results Of 66 patients included, 117 monitoring episodes were available. The mean age of the study population was 58.5 ± 16 years. 10 patients (15.2%) had mild, 28 (42.4%) moderate, and 28 (42.4%) severe ARDS. Nineteen patients (28.8%) required extracorporeal membrane oxygenation. Early hypercapnia was present in 39 patients (59.1%). Multivariable analysis did not show a significant association between early hypercapnia and impaired cerebrovascular autoregulation (B = 0.023 [95% CI − 0.054; 0.100], p = 0.556). Hypocapnia during the monitoring period was significantly associated with impaired cerebrovascular autoregulation [B = 0.155 (95% CI 0.014; 0.296), p = 0.032]. Conclusion Our results suggest that moderate permissive hypercapnia during the acute phase of ARDS has no adverse effect on cerebrovascular autoregulation and may be tolerated to a certain extent to achieve low tidal volumes. In contrast, episodes of hypocapnia may compromise cerebral blood flow regulation. Trial registration ClinicalTrials.gov; registration number: NCT03949738; date of registration: May 14, 2019